Compounds, compositions and methods

ABSTRACT

The present disclosure relates generally to methods and compositions for preventing or arresting cell death and/or inflammation.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a United States non-provisional continuationapplication filed under 35 U.S.C. § 111(a) of International PatentApplication No. PCT/US2017/065368, filed on Dec. 8, 2017, which claimspriority under 35 U.S.C. § 119(e) of U.S. Provisional Application No.62/432,412, filed Dec. 9, 2016, and U.S. Provisional Application No.62/526,942, filed on Jun. 29, 2017. The entire contents of each of theseapplications are incorporated by reference in their entirety into thisapplication.

FIELD

The present disclosure relates generally to methods and compositions forpreventing or arresting cell death and/or inflammation.

BACKGROUND

Programmed necrotic cell death, also called necroptosis, is a form ofcell death in which various stimuli such as TNFα, certain toll-likereceptor (TLR) agonists and ischemia can induce cellular necrosis.Necroptosis is a highly inflammatory form of cell death and is thoughtto be an important contributor to pathology in multiple degenerative andinflammatory diseases. These diseases include neurodegenerativediseases, stroke, coronary heart disease and myocardial infarction,retinal degenerative diseases, inflammatory bowel disease, kidneydisease, liver disease and others.

Necrosis is characterized by cell membrane and organelle disruption,cell swelling and mitochondrial impairment, followed by cell lysis.Also, cell lyses typically are accompanied by an inflammatory response.Some of the underlying biochemical events in this process are nowunderstood and the activity of receptor interacting protein kinase 1 hasbeen shown to be important for cells to undergo necroptosis.Furthermore, this activity is also known to promote the release ofinflammatory mediators such as TNF alpha from cells which can induceinflammation and also promote further necroptosis. Therefore,identifying and preparing low molecular weight molecules that preventnecrotic cell death and/or inflammation by inhibiting this or by othermechanisms can provide useful compounds for therapeutic intervention indiseases characterized by necrotic cell death and/or inflammation.

While progress has been made, there remains a need in the art forimproved compounds for preventing and treating diseases involving celldeath and/or inflammation. The present disclosure provides this andrelated benefits.

SUMMARY

Provided herein are compounds that are useful as inhibitors of receptorinteracting protein kinase 1. The disclosure also provides compositions,including pharmaceutical compositions, kits that include the compounds,and methods of using (or administering) and making the compounds. Thedisclosure further provides compounds or compositions thereof for use ina method of treating a disease, disorder, or condition that is mediatedby receptor interacting protein kinase 1. Moreover, the disclosureprovides uses of the compounds or compositions thereof in themanufacture of a medicament for the treatment of a disease, disorder orcondition that is mediated by (or mediated, at least in part, by)receptor interacting protein kinase 1.

In certain aspects, provided is a compound of any of Formulas I-XX, orsubformula thereof, or a pharmaceutically acceptable salt, prodrug,stereoisomer or a mixture of stereoisomers thereof. In certain aspects,provided is a compound as shown in Table 1 or a pharmaceuticallyacceptable salt, prodrug, stereoisomer or a mixture of stereoisomersthereof. In certain aspects, provided is a compound as shown in Table 2or a pharmaceutically acceptable salt, prodrug, stereoisomer or amixture of stereoisomers thereof. Also provided herein is apharmaceutical composition comprising a compound as described herein, ora pharmaceutically acceptable salt, prodrug, stereoisomer or a mixtureof stereoisomers thereof, and an excipient.

Provided herein are compounds and compositions for use in medicine. Incertain embodiments, the compounds and compositions are for use in thetreatment of a receptor interacting protein kinase 1-mediated disease ordisorder.

Provided herein is a method of treating a receptor interacting proteinkinase 1-mediated disease or disorder comprising administering atherapeutically effective amount of a compound or pharmaceuticalcomposition disclosed herein to a subject in need thereof.

In certain embodiments, the disease or disorder is inflammatory boweldisease, Crohn's disease, ulcerative colitis, psoriasis, retinaldetachment, retinitis pigmentosa, macular degeneration, pancreatitis,atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, SoJIA,systemic lupus erythematosus, Sjogren's syndrome, systemic scleroderma,anti-phospholipid syndrome, vasculitis, osteoarthritis, non-alcoholsteatohepatitis, alcohol steatohepatitis, autoimmune hepatitisautoimmune hepatobiliary diseases, primary sclerosing cholangitis,nephritis, Celiac disease, autoimmune ITP, transplant rejection,ischemia reperfusion injury of solid organs, sepsis, systemicinflammatory response syndrome, cerebrovascular accident, myocardialinfarction, Huntington's disease, Alzheimer's disease, Parkinson'sdisease, allergic diseases, asthma, atopic dermatitis, multiplesclerosis, type I diabetes, Wegener's granulomatosis, pulmonarysarcoidosis, Behcet's disease, interleukin-1 converting enzymeassociated fever syndrome, chronic obstructive pulmonary disease, tumornecrosis factor receptor-associated periodic syndrome, or peridontitis.In certain embodiments, the disease or disorder is trauma, ischemia,stroke, cardiac infarction, infection, Gaucher's disease, Krabbedisease, sepsis, Parkinson's disease, Alzheimer's disease, amyotrophiclateral sclerosis, Huntington's disease, HIV-associated dementia,retinal degenerative disease, glaucoma, age-related maculardegeneration, rheumatoid arthritis, psoriasis, psoriatic arthritis orinflammatory bowel disease. In certain embodiments, the disease ordisorder is Alzheimer's disease, amyotrophic lateral sclerosis (ALS),Friedreich's ataxia, Huntington's disease, Lewy body disease,Parkinson's disease, or spinal muscular atrophy. In certain embodiments,the disease or disorder is brain injury, spinal cord injury, dementia,stroke, Alzheimer's disease, amyotrophic lateral sclerosis (ALS/LouGehrig's Disease), Parkinson's disease, Huntington's disease, multiplesclerosis, diabetic neuropathy, polyglutamine (polyQ) diseases, stroke,Fahr disease, Menke's disease, Wilson's disease, cerebral ischemia, or aprion disorder.

DETAILED DESCRIPTION

The following description sets forth exemplary embodiments of thepresent technology. It should be recognized, however, that suchdescription is not intended as a limitation on the scope of the presentdisclosure but is instead provided as a description of exemplaryembodiments.

1. Definitions

As used in the present specification, the following words, phrases andsymbols are generally intended to have the meanings as set forth below,except to the extent that the context in which they are used indicatesotherwise.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —C(O)NH₂is attached through the carbon atom. A dash at the front or end of achemical group is a matter of convenience; chemical groups may bedepicted with or without one or more dashes without losing theirordinary meaning. A wavy line or a dashed line drawn through a line in aFormula indicates a specified point of attachment of a group. Unlesschemically or structurally required, no directionality orstereochemistry is indicated or implied by the order in which a chemicalgroup is written or named.

The prefix “C_(u-v)” indicates that the following group has from u to vcarbon atoms. For example, “C₁₋₆ alkyl” indicates that the alkyl grouphas from 1 to 6 carbon atoms.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. In certain embodiments, the term “about” includes the indicatedamount±10%. In certain embodiments, the term “about” includes theindicated amount±5%. In certain embodiments, the term “about” includesthe indicated amount±1%. Also, to the term “about X” includesdescription of “X”. Also, the singular forms “a” and “the” includeplural references unless the context clearly dictates otherwise. Thus,e.g., reference to “the compound” includes a plurality of such compoundsand reference to “the assay” includes reference to one or more assaysand equivalents thereof known to those skilled in the art.

“Alkyl” refers to an unbranched or branched saturated hydrocarbon chain.As used herein, alkyl has 1 to 20 carbon atoms (i.e., C₁₋₂₀ alkyl), 1 to12 carbon atoms (i.e., C₁₋₁₂ alkyl), 1 to 8 carbon atoms (i.e., C_(1-s)alkyl), 1 to 6 carbon atoms (i.e., C₁₋₆ alkyl) or 1 to 4 carbon atoms(i.e., C₁₋₄ alkyl). Examples of alkyl groups include methyl, ethyl,propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl,2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and3-methylpentyl. When an alkyl residue having a specific number ofcarbons is named by chemical name or identified by molecular formula,all positional isomers having that number of carbons may be encompassed;thus, for example, “butyl” includes n-butyl (i.e., —(CH₂)₃CH₃),sec-butyl (i.e., —CH(CH₃)CH₂CH₃), isobutyl (i.e., —CH₂CH(CH₃)₂) andtert-butyl (i.e., —C(CH₃)₃); and “propyl” includes n-propyl (i.e.,—(CH₂)₂CH₃) and isopropyl (i.e., —CH(CH₃)₂).

Certain commonly used alternative chemical names may be used. Forexample, a divalent group such as a divalent “alkyl” group, a divalent“aryl” group, etc., may also be referred to as an “alkylene” group or an“alkylenyl” group, an “arylene” group or an “arylenyl” group,respectively. Also, unless indicated explicitly otherwise, wherecombinations of groups are referred to herein as one moiety, e.g.arylalkyl or aralkyl, the last mentioned group contains the atom bywhich the moiety is attached to the rest of the molecule.

“Alkenyl” refers to an alkyl group containing at least one carbon-carbondouble bond and having from 2 to 20 carbon atoms (i.e., C₂₋₂₀ alkenyl),2 to 8 carbon atoms (i.e., C₂₋₈ alkenyl), 2 to 6 carbon atoms (i.e.,C₂₋₆ alkenyl) or 2 to 4 carbon atoms (i.e., C₂₋₄ alkenyl). Examples ofalkenyl groups include ethenyl, propenyl, butadienyl (including1,2-butadienyl and 1,3-butadienyl).

“Alkynyl” refers to an alkyl group containing at least one carbon-carbontriple bond and having from 2 to 20 carbon atoms (i.e., C₂₋₂₀ alkynyl),2 to 8 carbon atoms (i.e., C₂₋₈ alkynyl), 2 to 6 carbon atoms (i.e.,

C₂₋₆ alkynyl) or 2 to 4 carbon atoms (i.e., C₂₋₄ alkynyl). The term“alkynyl” also includes those groups having one triple bond and onedouble bond.

“Alkoxy” refers to the group “alkyl-O—”. Examples of alkoxy groupsinclude methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,sec-butoxy, n-pentoxy, n-hexoxy and 1,2-dimethylbutoxy.

“Alkoxyalkyl” refers to the group “alkyl-O-alkyl”.

“Alkylthio” refers to the group “alkyl-S—”.

“Acyl” refers to a group —C(O)R, wherein R is hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; eachof which may be optionally substituted, as defined herein. Examples ofacyl include formyl, acetyl, cyclohexylcarbonyl,cyclohexylmethyl-carbonyl and benzoyl.

“Amido” refers to both a “C-amido” group which refers to the group—C(O)NR^(y)R^(z) and an “N-amido” group which refers to the group—NR^(y)C(O)R^(z), wherein R^(y) and R^(z) are independently hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl orheteroaryl; each of which may be optionally substituted, as definedherein.

“Amino” refers to the group —NR^(y)R^(z) wherein R^(y) and R^(z) areindependently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may beoptionally substituted, as defined herein.

“Amidino” refers to —C(NR)(NR₂), wherein each R is independentlyhydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,heteroalkyl or heteroaryl; each of which may be optionally substituted,as defined herein.

“Aryl” refers to an aromatic carbocyclic group having a single ring(e.g. monocyclic) or multiple rings (e.g. bicyclic or tricyclic)including fused systems. As used herein, aryl has 6 to 20 ring carbonatoms (i.e., C₆₋₂₀ aryl), 6 to 18 carbon ring atoms (i.e., C₆₋₁₈ aryl),6 to 12 carbon ring atoms (i.e., C₆₋₁₂ aryl) or 6 to 10 carbon ringatoms (i.e., C₆₋₁₀ aryl). Examples of aryl groups include phenyl,naphthyl, fluorenyl and anthryl. Aryl, however, does not encompass oroverlap in any way with heteroaryl defined below. If one or more arylgroups are fused with a heteroaryl, the resulting ring system isheteroaryl. If one or more aryl groups are fused with a heterocyclyl,the resulting ring system is heterocyclyl.

“Arylalkyl” or “Aralkyl” refers to the group “aryl-alkyl-”.

“Carbamoyl” refers to both an “O-carbamoyl” group which refers to thegroup —O—C(O)NR^(y)R^(z) and an “N-carbamoyl” group which refers to thegroup —NR^(y)C(O)OR^(z), wherein R^(y) and R^(z) are independentlyhydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,heteroalkyl or heteroaryl; each of which may be optionally substituted,as defined herein.

“Carboxyl ester” or “ester” refer to both —OC(O)R and —C(O)OR, wherein Ris alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkylor heteroaryl; each of which may be optionally substituted, as definedherein.

“Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkylgroup having a single ring or multiple rings including fused, bridgedand spiro ring systems. The term “cycloalkyl” includes cycloalkenylgroups (i.e., the cyclic group having at least one double bond). As usedherein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C₃₋₂₀cycloalkyl), 3 to 15 ring carbon atoms (i.e., C₃₋₁₅ cycloalkyl), 3 to 12ring carbon atoms (i.e., C₃₋₁₂ cycloalkyl), 3 to 10 ring carbon atoms(i.e., C₃₋₁₀ cycloalkyl), 3 to 8 ring carbon atoms (i.e., C₃₋₈cycloalkyl) or 3 to 6 ring carbon atoms (i.e., C₃₋₆ cycloalkyl).Cycloalkyl also includes “spiro cycloalkyl” when there are two positionsfor substitution on the same carbon atom. Monocyclic radicals include,for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl. Polycyclic radicals include, for example,adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl andthe like. Further, the term cycloalkyl is intended to encompass anynon-aromatic ring which may be fused to an aryl ring, regardless of theattachment to the remainder of the molecule.

“Cycloalkylalkyl” refers to the group “cycloalkyl-alkyl-”.

“Guanidino” refers to —NRC(NR)(NR₂), wherein each R is hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl orheteroaryl; each of which may be optionally substituted, as definedherein.

“Imino” refers to a group —C(NR)R, wherein each R is independentlyhydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,heteroalkyl or heteroaryl; each of which may be optionally substituted,as defined herein.

“Imido” refers to a group —C(O)NRC(O)R, wherein each R is independentlyhydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,heteroalkyl or heteroaryl; each of which may be optionally substituted,as defined herein.

“Halogen” or “halo” includes fluoro, chloro, bromo and iodo.

“Haloalkyl” refers to an unbranched or branched alkyl group as definedabove, wherein one or more hydrogen atoms (e.g., one to five or one tothree) are replaced by a halogen. For example, where a residue issubstituted with more than one halogen, it may be referred to by using aprefix corresponding to the number of halogen moieties attached.Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”)or three (“tri”) halo groups, which may be, but are not necessarily, thesame halogen. Examples of haloalkyl include trifluoromethyl,difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl and thelike.

“Haloalkoxy” refers to an alkoxy group as defined above, wherein one ormore hydrogen atoms (e.g., one to five or one to three) are replaced bya halogen.

“Hydroxyalkyl” refers to an alkyl group as defined above, wherein one ormore hydrogen atoms (e.g., one to five or one to three) are replaced bya hydroxy group.

“Heteroalkyl” refers to an alkyl group in which one or more of thecarbon atoms (and any associated hydrogen atoms) are each independentlyreplaced with the same or different heteroatomic group, provided thepoint of attachment to the remainder of the molecule is through a carbonatom. The term “heteroalkyl” includes unbranched or branched saturatedchain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbonatoms may be independently replaced with the same or differentheteroatomic group. Heteroatomic groups include, but are not limited to,—NR—, —O—, —S—, —S(O)—, —S(O)₂—, and the like, where R is hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, orheteroaryl; each of which may be optionally substituted, as definedherein. Examples of heteroalkyl groups include —CH₂OCH₃, —CH₂SCH₃, and—CH₂NRCH₃, where R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may beoptionally substituted, as defined herein. As used herein, heteroalkylincludes 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbonatoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

“Heteroaryl” refers to an aromatic group (e.g., a 5-14 membered ringsystem) having a single ring, multiple rings or multiple fused rings,with one or more ring heteroatoms independently selected from nitrogen,oxygen and sulfur. As used herein, heteroaryl includes 1 to 20 ringcarbon atoms (i.e., C₁₋₂₀ heteroaryl), 1 to 13 ring carbon atoms (i.e.,C₃₋₁₂ heteroaryl), 3 to 12 ring carbon atoms (i.e., C₃₋₁₂ heteroaryl) or3 to 8 carbon ring atoms (i.e., C₃₋₈ heteroaryl); and 1 to 6heteroatoms, 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 ringheteroatoms, 1 to 2 ring heteroatoms or 1 ring heteroatom independentlyselected from nitrogen, oxygen and sulfur. Examples of heteroaryl groupsinclude azepinyl, acridinyl, benzimidazolyl, benzothiazolyl,benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl,benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,

1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl and thiophenyl (i.e., thienyl). Examples of thefused-heteroaryl rings include, but are not limited to,benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl,indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl andimidazo[1,5-a]pyridinyl, where the heteroaryl can be bound via eitherring of the fused system. Any aromatic ring, having a single or multiplefused rings, containing at least one heteroatom, is considered aheteroaryl regardless of the attachment to the remainder of the molecule(i.e., through any one of the fused rings). Heteroaryl does notencompass or overlap with aryl as defined above.

“Heteroarylalkyl” refers to the group “heteroaryl-alkyl-”.

“Heterocyclyl” refers to a saturated or unsaturated cyclic alkyl group,with one or more ring heteroatoms independently selected from nitrogen,oxygen and sulfur. The term “heterocyclyl” includes heterocycloalkenylgroups (i.e., the heterocyclyl group having at least one double bond),bridged-heterocyclyl groups, fused-heterocyclyl groups andspiro-heterocyclyl groups. A heterocyclyl may be a single ring ormultiple rings wherein the multiple rings may be fused, bridged orspiro, and may comprise one or more oxo (C═O) or N-oxide (N—O—)moieties. Any non-aromatic ring containing at least one heteroatom isconsidered a heterocyclyl, regardless of the attachment (i.e., can bebound through a carbon atom or a heteroatom). Further, the termheterocyclyl is intended to encompass any non-aromatic ring containingat least one heteroatom, which ring may be fused to an aryl orheteroaryl ring, regardless of the attachment to the remainder of themolecule. As used herein, heterocyclyl has 2 to 20 ring carbon atoms

(i.e., C₂₋₂₀ heterocyclyl), 2 to 12 ring carbon atoms (i.e., C₂₋₁₂heterocyclyl), 2 to 10 ring carbon atoms (i.e., C₂₋₁₀ heterocyclyl), 2to 8 ring carbon atoms (i.e., C₂₋₈ heterocyclyl), 3 to 12 ring carbonatoms (i.e., C₃₋₁₂ heterocyclyl), 3 to 8 ring carbon atoms (i.e., C₃₋₈heterocyclyl) or 3 to 6 ring carbon atoms (i.e., C₃₋₆ heterocyclyl);having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ringheteroatoms, 1 to 2 ring heteroatoms or 1 ring heteroatom independentlyselected from nitrogen, sulfur or oxygen. Examples of heterocyclylgroups include dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl,imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl and1,1-dioxo-thiomorpholinyl. Examples of the spiro-heterocyclyl ringsinclude bicyclic and tricyclic ring systems, such as2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl and6-oxa-1-azaspiro[3.3]heptanyl. Examples of the fused-heterocyclyl ringsinclude, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl,4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl and isoindolinyl,where the heterocyclyl can be bound via either ring of the fused system.

“Heterocyclylalkyl” refers to the group “heterocyclyl-alkyl-”.

“Oxime” refers to the group —CR(═NOH) wherein R is hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl orheteroaryl; each of which may be optionally substituted, as definedherein.

“Sulfonyl” refers to the group —S(O)₂R, where R is hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl orheteroaryl; each of which may be optionally substituted, as definedherein. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl,phenylsulfonyl and toluenesulfonyl.

“Sulfinyl” refers to the group —S(O)R, where R is hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl orheteroaryl; each of which may be optionally substituted, as definedherein. Examples of sulfinyl are methylsulfinyl, ethylsulfinyl,phenylsulfinyl and toluenesulfinyl.

“Sulfonamido” refers to the groups —SO₂NRR and —NRSO₂R, where each R isindependently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may beoptionally substituted, as defined herein.

“Alkylsulfonyl” refers to the group —S(O)₂R, where R is alkyl.

“Alkylsulfinyl” refers to the group —S(O)R, where R is alkyl.

The terms “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur and that thedescription includes instances where said event or circumstance occursand instances in which it does not. Also, the term “optionallysubstituted” refers to any one or more hydrogen atoms (e.g., one to fiveor one to three) on the designated atom or group may or may not bereplaced by a moiety other than hydrogen.

The term “substituted” used herein means any of the above groups (i.e.,alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy,cycloalkyl, aryl, heterocyclyl, heteroaryl, and/or heteroalkyl) whereinat least one hydrogen atom is replaced by a bond to a non-hydrogen atomsuch as, but not limited to alkyl, alkenyl, alkynyl, alkoxy, alkylthio,acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, carboxyl,carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanadino, halo,haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydrazine, hydrazone,imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl,alkylsulfonyl, alkylsulfinyl, thiocyanate, sulfinic acid, sulfonic acid,sulfonamido, thiol, thioxo, N-oxide, or —Si(R¹⁰⁰)₃ wherein each R¹⁰⁰ isindependently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl.

The term “substituted” used herein means any of the above groups (i.e.,alkyl, alkylene, alkoxy, haloalkoxy, aryl, cycloalkyl, haloalkyl,heterocyclyl, heteroaryl, hydroxylalkyl and/or alkoxyalkyl) wherein atleast one hydrogen atom is replaced by a bond to a non-hydrogen atomsuch as, but not limited to: an alkyl group, a haloalkyl group, ahalogen atom such as F, Cl, Br, and I; an alkenyl, a haloalkenyl group,an alkynyl group, a haloalkynyl group, a cyclic group such as an aryl,heteroaryl, cycloalkyl, or heterocyclyl group, an oxygen atom in groupssuch as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atomin groups such as thiol groups, thioalkyl groups, thiohaloalkyl groups,sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atomin groups such as amines, amides, alkylamines, dialkylamines,arylamines, alkylarylamines, diarylamines, N-oxides, imides, andenamines; a silicon atom in groups such as trialkylsilyl groups,dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilylgroups; and other heteroatoms in various other groups. “Substituted”also means any of the above groups in which one or more hydrogen atoms(e.g., one to five or one to three) are replaced by a higher-order bond(e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo,carbonyl, formyl, carboxyl, carbonate, and ester groups; and nitrogen ingroups such as imines, oximes, hydrazones, and nitriles.

In certain embodiments, “substituted” includes any of the above alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups inwhich one or more hydrogen atoms (e.g., one to five or one to three) areindependently replaced with deuterium, halo, cyano, nitro, azido, oxo,alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, —NR^(g)R^(h), —NR^(g)C(═O)R^(h), —NR^(g)C(═O)NR^(g)R^(h),—NR^(g)C(═O)OR^(h), —NR^(g)S(═O)₁₋₂R^(h), —C(═O)R^(g),

—C(═O)OR^(g), —OC(═O)OR^(g), —OC(═O)R^(g), —C(═O)NR^(g)R^(h),—OC(═O)NR^(g)R^(h), —OR^(g), —SR^(g), —S(═O)R^(g), —S(═O)₂R^(g),

—OS(═O)₁₋₂R^(g), —S(═O)₁₋₂OR^(g), —NR^(g)S(═O)₁₋₂NR^(g)R^(h),═NSO₂R^(g), ═NOR^(g), —S(═O)₁₋₂NR^(g)R^(h), —SF₅, —SCF₃ or

—OCF₃. “Substituted” also means any of the above groups in which one ormore hydrogen atoms (e.g., one to five or one to three) are replacedwith —C(═O)R^(g), —C(═O)OR^(g), —C(═O)NR^(g)R^(h), —CH₂SO₂R^(g),—CH₂SO₂NR^(g)R^(h). “Substituted” further means any of the above groupsin which one or more hydrogen atoms (e.g., one to five or one to three)are replaced by —NR^(g)S(O)₁₋₂NR^(g)R^(h), —CH₂S(O)R^(g),—CH₂S(O)NR^(g)R^(h), —OC(═O)OR^(g), —SF₅, —SCF₃ or —OCF₃. “Substituted”further means any of the above groups in which one or more hydrogenatoms (e.g., one to five or one to three) are replaced by a bond to anamino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy,alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl,and/or heteroarylalkyl group. In the foregoing, R^(g) and R^(h) and R¹are the same or different and independently hydrogen, halo, alkyl,alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,and/or heteroarylalkyl, or two of R^(g) and R^(h) and R^(i) are takentogether with the atoms to which they are attached to form aheterocyclyl ring optionally substituted with oxo, halo or alkyloptionally substituted with oxo, halo, amino, hydroxyl or alkoxy. In anembodiment, each of said hydrogen, alkyl, alkenyl, alkynyl, alkoxy,thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, and/or heteroarylalkyl areindependently optionally substituted with one or more (e.g., one to fiveor one to three) oxo, alkyl, halo, amino, hydroxyl or alkoxyl. Inaddition, each of the foregoing substituents may also be optionallysubstituted with one or more (e.g., one to five or one to three) of theabove substituents.

Polymers or similar indefinite structures arrived at by definingsubstituents with further substituents appended ad infinitum (e.g., asubstituted aryl having a substituted alkyl which is itself substitutedwith a substituted aryl group, which is further substituted by asubstituted heteroalkyl group, etc.) are not intended for inclusionherein. Unless otherwise noted, the maximum number of serialsubstitutions in compounds described herein is three. For example,serial substitutions of substituted aryl groups with two othersubstituted aryl groups are limited to ((substituted aryl)substitutedaryl) substituted aryl. Similarly, the above definitions are notintended to include impermissible substitution patterns (e.g., methylsubstituted with 5 fluorines or heteroaryl groups having two adjacentoxygen ring atoms). Such impermissible substitution patterns are wellknown to the skilled artisan. When used to modify a chemical group, theterm “substituted” may describe other chemical groups defined herein.Unless specified otherwise, where a group is described as optionallysubstituted, any substituents of the group are themselves unsubstituted.For example, in certain embodiments, the term “substituted alkyl” refersto an alkyl group having one or more substituents (e.g., one to five orone to three) including hydroxy, halo, alkoxy, acyl, oxo, amino,cycloalkyl, heterocyclyl, aryl and heteroaryl. In certain embodiments,the one or more substituents (e.g., one to five or one to three) may befurther substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy,cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which issubstituted. In certain embodiments, the substituents may be furthersubstituted with halo, alkyl, haloalkyl, alkoxy, hydroxy, cycloalkyl,heterocyclyl, aryl or heteroaryl, each of which is unsubstituted.

Any compound or Formula given herein, is also intended to representunlabeled forms as well as isotopically labeled forms of the compounds.Isotopically labeled compounds have structures depicted by the formulasgiven herein except that one or more atoms (e.g., one to five or one tothree) are replaced by an atom having a selected atomic mass or massnumber. Examples of isotopes that can be incorporated into the disclosedcompounds include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, chlorine and iodine, such as ²H, ³H, ¹¹C, ¹³C,¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I and ¹²⁵I,respectively. Various isotopically labeled compounds of the presentdisclosure, for example those into which radioactive isotopes such as³H, ¹³C and ¹⁴C are incorporated. Such isotopically labelled compoundsmay be useful in metabolic studies, reaction kinetic studies, detectionor imaging techniques, such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) including drug orsubstrate tissue distribution assays or in radioactive treatment ofpatients.

The disclosure also includes “deuterated analogs” of compounds describedherein in which from 1 to n hydrogens attached to a carbon atom is/arereplaced by deuterium, in which n is the number of hydrogens in themolecule. Such compounds exhibit increased resistance to metabolism andare thus useful for increasing the half-life of any compound whenadministered to a mammal, particularly a human. See, for example,Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,”Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds aresynthesized by means well known in the art, for example by employingstarting materials in which one or more hydrogens (e.g., one to five orone to three) have been replaced by deuterium.

Deuterium labelled or substituted therapeutic compounds of thedisclosure may have improved DMPK (drug metabolism and pharmacokinetics)properties, relating to distribution, metabolism and excretion (ADME).Substitution with heavier isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life, reduced dosage requirements and/oran improvement in therapeutic index. An ¹⁸F, ³H, ¹¹C labeled compoundmay be useful for PET or SPECT or other imaging studies. Isotopicallylabeled compounds of this disclosure and prodrugs thereof can generallybe prepared by carrying out the procedures disclosed in the schemes orin the examples and preparations described below by substituting areadily available isotopically labeled reagent for a non-isotopicallylabeled reagent. It is understood that deuterium in this context isregarded as a substituent in a compound described herein.

The concentration of such a heavier isotope, specifically deuterium, maybe defined by an isotopic enrichment factor. In the compounds of thisdisclosure any atom not specifically designated as a particular isotopeis meant to represent any stable isotope of that atom. Unless otherwisestated, when a position is designated specifically as “H” or “hydrogen”,the position is understood to have hydrogen at its natural abundanceisotopic composition. Accordingly, in the compounds of this disclosureany atom specifically designated as a deuterium (D) is meant torepresent deuterium.

In many cases, the compounds of this disclosure are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

Provided are also pharmaceutically acceptable salts, hydrates, solvates,tautomeric forms, stereoisomers and prodrugs of the compounds describedherein. “Pharmaceutically acceptable” or “physiologically acceptable”refer to compounds, salts, compositions, dosage forms and othermaterials which are useful in preparing a pharmaceutical compositionthat is suitable for veterinary or human pharmaceutical use.

The term “pharmaceutically acceptable salt” of a given compound refersto salts that retain the biological effectiveness and properties of thegiven compound and which are not biologically or otherwise undesirable.“Pharmaceutically acceptable salts” or “physiologically acceptablesalts” include, for example, salts with inorganic acids and salts withan organic acid. In addition, if the compounds described herein areobtained as an acid addition salt, the free base can be obtained bybasifying a solution of the acid salt. Conversely, if the product is afree base, an addition salt, particularly a pharmaceutically acceptableaddition salt, may be produced by dissolving the free base in a suitableorganic solvent and treating the solution with an acid, in accordancewith conventional procedures for preparing acid addition salts from basecompounds. Those skilled in the art will recognize various syntheticmethodologies that may be used to prepare nontoxic pharmaceuticallyacceptable addition salts. Pharmaceutically acceptable acid additionsalts may be prepared from inorganic and organic acids. Salts derivedfrom inorganic acids include hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid and the like. Salts derivedfrom organic acids include acetic acid, propionic acid, glycolic acid,pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid,maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluene-sulfonic acid, salicylic acid and the like. Likewise,pharmaceutically acceptable base addition salts can be prepared frominorganic and organic bases. Salts derived from inorganic bases include,by way of example only, sodium, potassium, lithium, ammonium, calciumand magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary and tertiary amines, such asalkyl amines (i.e., NH₂(alkyl)), dialkyl amines (i.e., HN(alkyl)₂),trialkyl amines (i.e., N(alkyl)₃), substituted alkyl amines (i.e.,NH₂(substituted alkyl)), di(substituted alkyl) amines (i.e.,HN(substituted alkyl)₂), tri(substituted alkyl) amines (i.e.,N(substituted alkyl)₃), alkenyl amines (i.e., NH₂(alkenyl)), dialkenylamines (i.e., HN(alkenyl)₂), trialkenyl amines (i.e., N(alkenyl)₃),substituted alkenyl amines (i.e., NH₂(substituted alkenyl)),di(substituted alkenyl) amines (i.e., HN(substituted alkenyl)₂),tri(substituted alkenyl) amines (i.e., N(substituted alkenyl)₃, mono-,di- or tri-cycloalkyl amines (i.e., NH₂(cycloalkyl), HN(cycloalkyl)₂,N(cycloalkyl)₃), mono-, di- or tri-arylamines (i.e., NH₂(aryl),HN(aryl)₂, N(aryl)₃) or mixed amines, etc. Specific examples of suitableamines include, by way of example only, isopropylamine, trimethyl amine,diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine,2-dimethylaminoethanol, piperazine, piperidine, morpholine,N-ethylpiperidine and the like.

The term “hydrate” refers to the complex formed by the combining of acompound described herein and water.

A “solvate” refers to an association or complex of one or more solventmolecules and a compound of the disclosure. Examples of solvents thatform solvates include, but are not limited to, water, isopropanol,ethanol, methanol, dimethylsulfoxide, ethylacetate, acetic acid andethanolamine.

Some of the compounds exist as tautomers. Tautomers are in equilibriumwith one another. For example, amide containing compounds may exist inequilibrium with imidic acid tautomers. Regardless of which tautomer isshown and regardless of the nature of the equilibrium among tautomers,the compounds are understood by one of ordinary skill in the art tocomprise both amide and imidic acid tautomers. Thus, the amidecontaining compounds are understood to include their imidic acidtautomers. Likewise, the imidic acid containing compounds are understoodto include their amide tautomers.

The compounds disclosed herein, or their pharmaceutically acceptablesalts include an asymmetric center and may thus give rise toenantiomers, diastereomers, and other stereoisomeric forms that may bedefined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)- for amino acids. The disclosure is meant to include allsuch possible isomers, as well as their racemic and optically pureforms. Optically active (+) and (−), (R)- and (S)-, or (D)- and(L)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques, for example, chromatography andfractional crystallization. Conventional techniques for thepreparation/isolation of individual enantiomers include chiral synthesisfrom a suitable optically pure precursor or resolution of the racemate(or the racemate of a salt or derivative) using, for example, chiralhigh pressure liquid chromatography (HPLC). When the compounds describedherein contain olefinic double bonds or other centres of geometricasymmetry, and unless specified otherwise, it is intended that thecompounds include both E and Z geometric isomers. Likewise, alltautomeric forms are also intended to be included.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present disclosure contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are nonsuperimposeablemirror images of one another.

“Diastereoisomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other.

“Prodrugs” means any compound which releases an active parent drugaccording to a Formula described herein in vivo when such prodrug isadministered to a mammalian subject. Prodrugs of a compound describedherein are prepared by modifying functional groups present in thecompound described herein in such a way that the modifications may becleaved in vivo to release the parent compound. Prodrugs may be preparedby modifying functional groups present in the compounds in such a waythat the modifications are cleaved, either in routine manipulation or invivo, to the parent compounds. Prodrugs include compounds describedherein wherein a hydroxy, amino, carboxyl or sulfhydryl group in acompound described herein is bonded to any group that may be cleaved invivo to regenerate the free hydroxy, amino or sulfhydryl group,respectively. Examples of prodrugs include, but are not limited toesters (e.g., acetate, formate and benzoate derivatives), amides,guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxyfunctional groups in compounds described herein and the like.Preparation, selection and use of prodrugs is discussed in T. Higuchiand V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of theA.C.S. Symposium Series; “Design of Prodrugs,” ed. H. Bundgaard,Elsevier, 1985; and in Bioreversible Carriers in Drug Design, ed. EdwardB. Roche, American Pharmaceutical Association and Pergamon Press, 1987,each of which are hereby incorporated by reference in their entirety.

As used herein, “pharmaceutically acceptable carrier” or“pharmaceutically acceptable excipient” or “excipient” includes any andall solvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents and the like. The use ofsuch media and agents for pharmaceutically active substances is wellknown in the art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

The term “necrotic cell disease” refers to diseases associated with orcaused by cellular necrosis. Exemplary necrotic cell diseases include,but are not limited to, acute diseases such as trauma, ischemia, stroke,cardiac infarction, anthrax lethal toxin induced septic shock, sepsis,cell death induced by LPS and HIV induced T-cell death leading toimmunodeficiency. The term “necrotic cell disease” also includes but isnot limited to chronic neurodegenerative diseases, such as Parkinson'sdisease, Huntington's disease, amyotrophic lateral sclerosis,Alzheimer's disease, infectious encelopathies, dementia such as HIVassociated dementia. The term “necrotic cell disease” also includes butis not limited to diseases such as inflammatory bowel disease and acuteand chronic kidney disease which are characterized by inflammation andcell death.

The chemical names used herein are generated using the MarvinSketchVersion 6.1.6 (ChemAxon) or the ChemDraw Ultra Version 13.0 softwarenaming programs.

2. Compounds

Provided are compounds of Formula I:

or a pharmaceutically acceptable salt, prodrug, stereoisomer or amixture of stereoisomers thereof, wherein:

Y is N or CH;

n is 1 or 2;

m is 0, 1, 2, 3, 4 or 5;

p is 0, 1, 2 or 3;

A is aryl, heteroaryl, C₃₋₁₀ cycloalkyl or heterocyclyl;

each of R¹ and R² are independently hydrogen, deuterium, halo, C₁₋₁₂alkyl, C₁₋₁₂ alkenyl, C₁₋₁₂ alkynyl, C₁₋₁₂ alkoxy, C₁₋₁₂ haloalkyl,C₁₋₁₂ haloalkoxy, C₃₋₁₀ cycloalkyl, heterocyclyl, heteroaryl or aryl;

-   -   wherein each C₁₋₁₂ alkyl, C₁₋₁₂ alkenyl, C₁₋₁₂ alkynyl, C₁₋₁₂        alkoxy, C₁₋₁₂ haloalkyl, C₁₋₁₂ haloalkoxy, C₃₋₁₀ cycloalkyl,        heterocyclyl, heteroaryl and aryl are optionally substituted        with one, two, three, four or five Z¹; or

R¹ and R² taken together with the atom to which they are attached toform a C₃₋₁₀ cycloalkyl; wherein the C₃₋₁₀ cycloalkyl is optionallysubstituted with one, two, three, four or five Z²;

R³ in each instance is independently deuterium, halo, hydroxy, cyano,nitro, azido, oxo, C₁₋₁₂ alkyl,

—OR⁵, C₁₋₁₂ alkoxy, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂ haloalkyl, C₁₋₁₂haloalkoxy, C₃₋₁₀ cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R⁴,—C(═O)OR⁴, —OC(═O)OR⁴, —OC(═O)R⁴, —C(═O)NR⁴R⁵, —OC(═O)NR⁴R⁵,—NR⁴C(═O)NR⁵R⁶, —S(═O)₁₋₂R⁴, —S(═O)₁₋₂OR⁴, —OS(═O)₁₋₂R⁴, —S(═O)₁₋₂NR⁴,—NR⁴S(═O)₁₋₂R⁵, —NR⁴S(═O)₁₋₂NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵ or —NR⁴C(═O)OR⁵;wherein each C₁₋₁₂ alkyl, C₁₋₁₂ alkoxy, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl,C₁₋₁₂ haloalkyl, C₁₋₁₂ haloalkoxy, C₃₋₁₀ cycloalkyl, heterocyclyl, aryland heteroaryl are optionally substituted with one, two, three, four orfive Z³;

R⁴, R⁵, and R⁶ in each instance are independently C₁₋₁₂ alkyl, C₁₋₁₂alkenyl, C₁₋₁₂ alkynyl, C₁₋₁₂ haloalkyl, C₃₋₁₀ cycloalkyl, heterocyclyl,heteroaryl or aryl; wherein each C₁₋₁₂ alkyl, C₁₋₁₂ alkenyl, C₁₋₁₂alkynyl, C₁₋₁₂ haloalkyl, C₃₋₁₀ cycloalkyl, heterocyclyl, heteroaryl andaryl are optionally substituted with one, two, three, four or five Z⁴;or

two of R⁴, R⁵, and R⁶ taken together with the atoms to which they areattached to form a heterocyclyl; wherein the heterocyclyl is optionallysubstituted with one, two, three, four or five Z⁵;

R¹⁴ can be bonded to either ring of the fused bicyclic ring and, in eachinstance, is independently halo, haloalkyl, or two R¹⁴ bonded to thesame carbon atom may be taken together with the atom to which they areattached to form a C₃₋₁₀ cycloalkyl or heterocyclyl; wherein the C₃₋₁₀cycloalkyl or heterocyclyl is optionally substituted with one, two,three, four or five Z⁶;

each of Z¹, Z², Z³, Z⁴, Z⁵ and Z⁶ are independently deuterium, halo,hydroxy, cyano, nitro, azido, C₁₋₁₂ alkyl, C₁₋₁₂ alkenyl, C₁₋₁₂ alkynyl,C₁₋₁₂ alkoxy, C₁₋₁₂ haloalkyl, C₁₋₁₂ haloalkoxy, C₃₋₁₀ cycloalkyl,heterocyclyl, aryl, heteroaryl, —C(═O)R¹¹, —C(═O)OR¹¹, —OC(═O)OR¹¹,—OC(═O)R¹¹, —C(═O)NR¹¹R¹², —OC(═O)NR¹¹R¹², —NR¹¹C(═O)NR¹²R¹³,—S(═O)₁₋₂R¹¹, —S(═O)₁₋₂OR¹¹, —S(═O)₁₋₂NR¹¹, —NR¹¹S(═O)₁₋₂R¹²,—NR¹¹S(═O)₁₋₂NR¹²R¹³, —NR¹¹R¹², —NR¹¹C(═O)R¹² or —NR¹¹C(═O)OR¹²;

-   -   wherein each C₁₋₁₂ alkyl, C₁₋₁₂ alkenyl, C₁₋₁₂ alkynyl, C₁₋₁₂        alkoxy, C₁₋₁₂ haloalkyl, C₁₋₁₂ haloalkoxy, C₃₋₁₀ cycloalkyl,        heterocyclyl, aryl and heteroaryl, are optionally substituted        with one, two or three substituents independently selected from        deuterium, halo, hydroxy, cyano, amino, nitro, azido, oxo, C₁₋₁₂        alkyl, C₁₋₁₂ alkoxy, C₁₋₁₂ haloalkyl, C₁₋₁₂ haloalkoxy, C₂₋₁₂        alkenyl, C₂₋₁₂ alkynyl,

C₃₋₁₀ cycloalkyl, heterocyclyl, aryl and heteroaryl; and

R¹¹, R¹², and R¹³ in each instance are independently C₁₋₁₂ alkyl, C₁₋₁₂alkenyl, C₁₋₁₂ alkynyl, C₁₋₁₂ alkoxy, C₃₋₁₀ cycloalkyl, heterocyclyl,heteroaryl or aryl; wherein each C₁₋₁₂ alkyl, C₁₋₁₂ alkenyl, C₁₋₁₂alkynyl, C₁₋₁₂ alkoxy, C₃₋₁₀ cycloalkyl, heterocyclyl, heteroaryl andaryl are optionally substituted with one, two, three, four or five Z¹¹;or

two of R¹¹, R¹², and R¹³ are taken together with the atoms to which theyare attached to form a heterocyclyl; wherein the heterocyclyl isoptionally substituted with one, two, three, four or five Z¹²;

each of Z¹¹ and Z¹² is independently deuterium, halo, hydroxy, cyano,oxo, amino or C₁₋₁₂ alkyl; wherein the C₁₋₁₂ alkyl is optionallysubstituted with one, two or three halo, hydroxyl, amino or oxo. Incertain embodiments, at least one of R¹ and R² is C₁₋₁₂ alkyl, C₁₋₁₂alkenyl, C₁₋₁₂ alkynyl, C₁₋₁₂ haloalkyl, C₃₋₁₀ cycloalkyl, heterocyclyl,heteroaryl or aryl; wherein each C₁₋₁₂ alkyl, C₁₋₁₂ alkenyl, C₁₋₁₂alkynyl, C₁₋₁₂ haloalkyl, C₃₋₁₀ cycloalkyl, heterocyclyl, heteroaryl andaryl are optionally substituted with one, two, three, four or five Z¹;or

R¹ and R² taken together with the atoms to which they are attached toform a C₃₋₁₀ cycloalkyl; wherein the C₃₋₁₀ cycloalkyl is optionallysubstituted with one, two, three, four or five Z².

In certain embodiments, the compound is nothexahydro-6-methyl-3-phenyl-5(1H)-indolizinone,6-[(2-bromo-1H-indol-3-yl)methyl]hexahydro-3-(4-hydroxyphenyl)-5(1H)-indolizinone,or a stereoisomer thereof.

In certain embodiments, the compound is nothexahydro-6-[hydroxy[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methyl]-3-(3,4,5-trifluorophenyl)-5(1H)-indolizinone,3-(3,4-difluorophenyl)hexahydro-6-[hydroxy[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]methyl]-5(1H)-indolizinone,or a stereoisomer thereof.

In certain embodiments, the compound is not

or a stereoisomer, mixture of stereoisomers or tautomer thereof.

In certain embodiments, R¹ is —C(R^(1a))(R^(1b))(R^(1c)), wherein eachof R^(1a), R^(1b) and R^(1c) is independently deuterium, halo, hydroxy,cyano, nitro, azido, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂alkoxy, C₁₋₁₂ haloalkyl, C₁₋₁₂ haloalkoxy, C₃₋₁₀ cycloalkyl,heterocyclyl, aryl, heteroaryl, —C(═O)R¹¹, —C(═O)OR¹¹,

—OC(═O)OR¹¹, —OC(═O)R¹¹, —C(═O)NR¹¹R¹², —OC(═O)NR¹¹R¹²,—NR¹¹C(═O)NR¹²R¹³, —S(═O)₁₂R¹¹, —S(═O)₁₋₂OR¹¹, —S(═O)₁₋₂NR¹¹,—NR¹¹S(═O)₁₂R¹², —NR¹¹S(═O)₁₋₂NR¹²R¹³, —NR¹¹R¹², —NR¹¹C(═O)R¹² or—NR¹¹C(═O)OR¹²; wherein each C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl,C₁₋₁₂ alkoxy, C₁₋₁₂ haloalkyl, C₁₋₁₂ haloalkoxy, C₃₋₁₀ cycloalkyl,heterocyclyl, aryl and heteroaryl are optionally substituted with one,two or three Z⁷;

Z⁷ is deuterium, halo, hydroxy, cyano, amino, nitro, azido, oxo, C₁₋₁₂alkyl, C₁₋₁₂ alkoxy, C₁₋₁₂ haloalkyl, C₁₋₁₂ haloalkoxy, C₂₋₁₂ alkenyl,C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl, heterocyclyl, aryl or heteroaryl; and

R¹¹, R¹² and R¹³ are as defined herein.

In certain embodiments, provided are compounds of Formula Ia:

or a pharmaceutically acceptable salt, prodrug, stereoisomer or amixture of stereoisomers thereof, wherein:

Y is N or CH;

n is 1 or 2;

m is 0, 1, 2, 3, 4 or 5;

p is 0, 1, 2 or 3;

A is aryl, heteroaryl, C₃₋₁₀ cycloalkyl or heterocyclyl;

each of R^(1a), R^(1b) and R^(1c) is independently deuterium, halo,hydroxy, cyano, nitro, azido, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl,C₁₋₁₂ alkoxy, C₁₋₁₂ haloalkyl, C₁₋₁₂ haloalkoxy, C₃₋₁₀ cycloalkyl,heterocyclyl, aryl, heteroaryl, —C(═O)R¹¹, —C(═O)OR¹¹, —OC(═O)OR¹¹,—OC(═O)R¹¹, —C(═O)NR¹¹R¹², —OC(═O)NR¹¹R¹²,

—NR¹¹C(═O)NR¹²R¹³, —S(═O)₁₋₂R¹¹, —S(═O)₁₋₂OR¹¹, —S(═O)₁₋₂NR¹¹,—NR¹¹S(═O)₁₋₂R¹², —NR¹¹S(═O)₁₋ ₂NR¹²R¹³, —NR¹¹R¹², —NR¹¹C(═O)R¹² or—NR¹¹C(═O)OR¹²; wherein each C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl,C₁₋₁₂ alkoxy, C₁₋₁₂ haloalkyl, C₁₋₁₂ haloalkoxy, C₃₋₁₀ cycloalkyl,heterocyclyl, aryl and heteroaryl are optionally substituted with one,two or three Z⁷;

R² is hydrogen, deuterium, halo, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂alkynyl, C₁₋₁₂ alkoxy, C₁₋₁₂ haloalkyl, C₁₋₁₂ haloalkoxy, C₃₋₁₀cycloalkyl, heterocyclyl, heteroaryl or aryl; wherein each C₁₋₁₂ alkyl,C₂₋₁₂ alkenyl,

C₂₋₁₂ alkynyl, C₁₋₁₂ alkoxy, C₁₋₁₂ haloalkyl, C₁₋₁₂ haloalkoxy, C₃₋₁₀cycloalkyl, heterocyclyl, heteroaryl and aryl are optionally substitutedwith one, two, three, four or five Z¹; or

any two of R^(1a), R^(1b) or R^(1c) and R² are taken together with theatom to which they are attached to form a C₃₋₁₀ cycloalkyl orheterocyclyl; wherein the C₃₋₁₀ cycloalkyl or heterocyclyl is optionallysubstituted with one, two, three, four or five Z²;

R³ in each instance is independently deuterium, halo, hydroxy, cyano,nitro, azido, oxo, C₁₋₁₂ alkyl,

—OR⁵, C₁₋₁₂ alkoxy, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂ haloalkyl, C₁₋₁₂haloalkoxy, C₃₋₁₀ cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R⁴,—C(═O)OR⁴, —OC(═O)OR⁴, —OC(═O)R⁴, —C(═O)NR⁴R⁵, —OC(═O)NR⁴R⁵,—NR⁴C(═O)NR⁵R⁶, —S(═O)₁₋₂R⁴, —S(═O)₁₋₂OR⁴, —OS(═O)₁₋₂R⁴, —S(═O)₁₋₂NR⁴,—NR⁴S(═O)₁₋₂R⁵, —NR⁴S(═O)₁₋₂NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵ or —NR⁴C(═O)OR⁵;wherein each C₁₋₁₂ alkyl, C₁₋₁₂ alkoxy, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl,C₁₋₁₂ haloalkyl, C₁₋₁₂ haloalkoxy, C₃₋₁₀ cycloalkyl, heterocyclyl, aryland heteroaryl are optionally substituted with one, two, three, four orfive Z³;

R⁴, R⁵, and R⁶ in each instance are independently C₁₋₁₂ alkyl, C₁₋₁₂alkenyl, C₁₋₁₂ alkynyl, C₁₋₁₂ haloalkyl, C₃₋₁₀ cycloalkyl, heterocyclyl,heteroaryl or aryl; wherein each C₁₋₁₂ alkyl, C₁₋₁₂ alkenyl, C₁₋₁₂alkynyl, C₁₋₁₂ haloalkyl, C₃₋₁₀ cycloalkyl, heterocyclyl, heteroaryl andaryl are optionally substituted with one, two, three, four or five Z⁴;or

two of R⁴, R⁵, and R⁶ taken together with the atoms to which they areattached to form a heterocyclyl; wherein the heterocyclyl is optionallysubstituted with one, two, three, four or five Z⁵;

R¹⁴ can be bonded to either ring of the fused bicyclic ring and, in eachinstance, is independently halo, haloalkyl, or two R¹⁴ bonded to thesame carbon atom may be taken together with the atom to which they areattached to form a C₃₋₁₀ cycloalkyl or heterocyclyl; wherein the C₃₋₁₀cycloalkyl or heterocyclyl is optionally substituted with one, two,three, four or five Z⁶;

each of Z¹, Z², Z³, Z⁴, Z⁵ and Z⁶ are independently deuterium, halo,hydroxy, cyano, nitro, azido, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl,C₁₋₁₂ alkoxy, C₁₋₁₂ haloalkyl, C₁₋₁₂ haloalkoxy, C₃₋₁₀ cycloalkyl,heterocyclyl, aryl, heteroaryl, —C(═O)R¹¹, —C(═O)OR¹¹, —OC(═O)OR¹¹,—OC(═O)R¹¹, —C(═O)NR¹¹R¹², —OC(═O)NR¹¹R¹², —NR¹¹C(═O)NR¹²R¹³,—S(═O)₁₋₂R¹¹, —S(═O)₁₋₂ OR¹¹, —S(═O)₁₋₂NR¹¹, —NR¹¹S(═O)₁₋₂R¹²,—NR¹¹S(═O)₁₋₂NR¹²R¹³, —NR¹¹R¹², —NR¹¹C(═O)R¹² or —NR¹¹C(═O)OR¹²;

-   -   wherein each C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂        alkoxy, C₁₋₁₂ haloalkyl, C₁₋₁₂ haloalkoxy, C₃₋₁₀ cycloalkyl,        heterocyclyl, aryl and heteroaryl, are optionally substituted        with one, two or three substituents independently selected from        deuterium, halo, hydroxy, cyano, amino, nitro, azido, oxo, C₁₋₁₂        alkyl, C₁₋₁₂ alkoxy, C₁₋₁₂ haloalkyl, C₁₋₁₂ haloalkoxy, C₂₋₁₂        alkenyl, C₂₋₁₂ alkynyl,

C₃₋₁₀ cycloalkyl, heterocyclyl, aryl and heteroaryl;

Z⁷ is deuterium, halo, hydroxy, cyano, amino, nitro, azido, oxo, C₁₋₁₂alkyl, C₁₋₁₂ alkoxy, C₁₋₁₂ haloalkyl, C₁₋₁₂ haloalkoxy, C₂₋₁₂ alkenyl,C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl, heterocyclyl, aryl or heteroaryl;

R¹¹, R¹², and R¹³ in each instance are independently C₁₋₁₂ alkyl, C₁₋₁₂alkenyl, C₁₋₁₂ alkynyl, C₁₋₁₂ alkoxy, C₃₋₁₀ cycloalkyl, heterocyclyl,heteroaryl or aryl; wherein each C₁₋₁₂ alkyl, C₁₋₁₂ alkenyl, C₁₋₁₂alkynyl, C₁₋₁₂ alkoxy, C₃₋₁₀ cycloalkyl, heterocyclyl, heteroaryl andaryl are optionally substituted with one, two, three, four or five Z¹¹;or

two of R¹¹, R¹², and R¹³ are taken together with the atoms to which theyare attached to form a heterocyclyl; wherein the heterocyclyl isoptionally substituted with one, two, three, four or five Z¹²; and

each of Z¹¹ and Z¹² is independently deuterium, halo, hydroxy, cyano,oxo, amino or C₁₋₁₂ alkyl; wherein the C₁₋₁₂ alkyl is optionallysubstituted with one, two or three halo, hydroxyl, amino or oxo.

In certain embodiments, the compound is nothexahydro-6-methyl-3-phenyl-5(1H)-indolizinone,6-[(2-bromo-1H-indol-3-yl)methyl]hexahydro-3-(4-hydroxyphenyl)-5(1H)-indolizinone,or a stereoisomer thereof.

In certain embodiments, provided are compounds of Formula Ib:

or a pharmaceutically acceptable salt, prodrug, stereoisomer or amixture of stereoisomers thereof, wherein:

Y is N or CH;

n is 1 or 2;

m is 0, 1, 2, 3, 4 or 5;

A is aryl, heteroaryl, C₃₋₁₀ cycloalkyl or heterocyclyl;

each of R¹ and R² are independently hydrogen, deuterium, halo, C₁₋₁₂alkyl, C₁₋₁₂ alkenyl, C₁₋₁₂ alkynyl, C₁₋₁₂ alkoxy, C₁₋₁₂ haloalkyl,C₁₋₁₂ haloalkoxy, C₃₋₁₀ cycloalkyl, heterocyclyl, heteroaryl or aryl;wherein each C₁₋₁₂ alkyl, C₁₋₁₂ alkenyl, C₁₋₁₂ alkynyl, C₁₋₁₂ alkoxy,C₁₋₁₂ haloalkyl, C₁₋₁₂ haloalkoxy, C₃₋₁₀ cycloalkyl, heterocyclyl,heteroaryl and aryl are optionally substituted with one, two, three,four or five Z¹; or

R¹ and R² taken together with the atoms to which they are attached toform a C₃₋₁₀ cycloalkyl; wherein the C₃₋₁₀ cycloalkyl is optionallysubstituted with one, two, three, four or five Z²;

R³ in each instance is independently deuterium, halo, hydroxy, cyano,nitro, azido, oxo, C₁₋₁₂ alkyl,

—OR⁵, C₁₋₁₂ alkoxy, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂ haloalkyl, C₁₋₁₂haloalkoxy, C₃₋₁₀ cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R⁴,—C(═O)OR⁴, —OC(═O)OR⁴, —OC(═O)R⁴, —C(═O)NR⁴R⁵, —OC(═O)NR⁴R⁵,—NR⁴C(═O)NR⁵R⁶, —S(═O)₁₋₂R⁴, —S(═O)₁₋₂OR⁴, —OS(═O)₁₋₂R⁴, —S(═O)₁₋₂NR⁴,—NR⁴S(═O)₁₋₂R⁵, —NR⁴S(═O)₁₋₂NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵ or —NR⁴C(═O)OR⁵;wherein each C₁₋₁₂ alkyl, C₁₋₁₂ alkoxy, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl,C₁₋₁₂ haloalkyl, C₁₋₁₂ haloalkoxy, C₃₋₁₀ cycloalkyl, heterocyclyl, aryland heteroaryl are optionally substituted with one, two, three, four orfive Z³;

R⁴, R⁵, and R⁶ in each instance are independently C₁₋₁₂ alkyl, C₁₋₁₂alkenyl, C₁₋₁₂ alkynyl, C₁₋₁₂ haloalkyl, C₃₋₁₀ cycloalkyl, heterocyclyl,heteroaryl or aryl; wherein each C₁₋₁₂ alkyl, C₁₋₁₂ alkenyl, C₁₋₁₂alkynyl, C₁₋₁₂ haloalkyl, C₃₋₁₀ cycloalkyl, heterocyclyl, heteroaryl andaryl are optionally substituted with one, two, three, four or five Z⁴;or

two of R⁴, R⁵, and R⁶ taken together with the atoms to which they areattached to form a heterocyclyl; wherein the heterocyclyl is optionallysubstituted with one, two, three, four or five Z⁵;

each of Z¹, Z², Z³, Z⁴ and Z⁵ are independently deuterium, halo,hydroxy, cyano, nitro, azido, C₁₋₁₂ alkyl, C₁₋₁₂ alkenyl, C₁₋₁₂ alkynyl,C₁₋₁₂ alkoxy, C₁₋₁₂ haloalkyl, C₁₋₁₂ haloalkoxy, C₃₋₁₀ cycloalkyl,heterocyclyl, aryl, heteroaryl, —C(═O)R¹¹, —C(═O)OR¹¹, —OC(═O)OR¹¹,—OC(═O)R¹¹, —C(═O)NR¹¹R¹², —OC(═O)NR¹¹R¹², —NR¹¹C(═O)NR¹²R¹³,—S(═O)₁₋₂R¹¹, —S(═O)₁₋₂OR¹¹, —S(═O)₁₋₂NR¹¹, —NR¹¹S(═O)₁₋₂R¹²,—NR¹¹S(═O)₁₂NR¹²R¹³, —NR¹¹R¹², —NR¹¹C(═O)R¹² or —NR¹¹C(═O)OR¹²;

-   -   wherein each C₁₋₁₂ alkyl, C₁₋₁₂ alkenyl, C₁₋₁₂ alkynyl, C₁₋₁₂        alkoxy, C₁₋₁₂ haloalkyl, C₁₋₁₂ haloalkoxy, C₃₋₁₀ cycloalkyl,        heterocyclyl, aryl and heteroaryl, are optionally substituted        with one, two or three substituents independently selected from        deuterium, halo, hydroxy, cyano, amino, nitro, azido, oxo, C₁₋₁₂        alkyl, C₁₋₁₂ alkoxy, C₁₋₁₂ haloalkyl, C₁₋₁₂ haloalkoxy, C₂₋₁₂        alkenyl, C₂₋₁₂ alkynyl,

C₃₋₁₀ cycloalkyl, heterocyclyl, aryl and heteroaryl; and

R¹¹, R¹², and R¹³ in each instance are independently C₁₋₁₂ alkyl, C₁₋₁₂alkenyl, C₁₋₁₂ alkynyl, C₁₋₁₂ alkoxy, C₃₋₁₀ cycloalkyl, heterocyclyl,heteroaryl or aryl; wherein each C₁₋₁₂ alkyl, C₁₋₁₂ alkenyl, C₁₋₁₂alkynyl, C₁₋₁₂ alkoxy, C₃₋₁₀ cycloalkyl, heterocyclyl, heteroaryl andaryl are optionally substituted with one, two, three, four or five Z¹¹;or

two of R¹¹, R¹², and R¹³ are taken together with the atoms to which theyare attached to form a heterocyclyl; wherein the heterocyclyl isoptionally substituted with one, two, three, four or five Z¹²;

each of Z¹¹ and Z¹² is independently deuterium, halo, hydroxy, cyano,oxo, amino or C₁₋₁₂ alkyl; wherein the C₁₋₁₂ alkyl is optionallysubstituted with one, two or three halo, hydroxyl, amino or oxo.

In certain embodiments, when n is 1, Y is CH and one of R¹ and R² isiodo, both of R¹ and R² are hydrogen, or one of R¹ and R² is alkenyl,then A is not 3,4-difluorophenyl, and when n is 1, Y is CH, both of R¹and R² are hydrogen, then A is not heterocyclyl substituted with oxo.

In certain embodiments, when n is 2, Y is CH and one of R¹ or R² isiodo, or both of R¹ or R² are hydrogen, then A is not 4-chlorophenyl,2,6-difluoropyridin-3-yl, phenyl, or phenyl substituted with 1, 2 or 3fluoro, and the compound is not(3R,8aR)-6-chloro-3-(4-fluorophenyl)hexahydroindolizin-5(1H)-one;(3R,6S,8aS)-6-methyl-3-phenylhexahydroindolizin-5(1H)-one; or(3R,6R,8aS)-6-((2-bromo-1H-indol-3-yl)methyl)-3-(4-hydroxyphenyl)hexahydroindolizin-5(1H)-one.

In certain embodiments, provided is a compound of formula Ia′:

where A, Y, n, m, p, R^(1a), R^(1b), R^(1c), R², R³ and R¹⁴ are asdefined herein. In certain embodiments, provided is a compound offormula Ia″:

where A, Y, n, m, p, R^(1a), R^(1b), R^(1c), R², R³ and R¹⁴ are asdefined herein. In certain embodiments, provided is a compound offormula Ib′:

where A, Y, n, m, R¹, R² and R³ are as defined herein. In certainembodiments, provided is a compound of formula Ib″:

where A, Y, n, m, R¹, R² and R³ are as defined herein.

In certain embodiments, provided is a compound of formula Ic:

where Y, n, m, p, R¹, R², R³ and R¹⁴ are as defined herein. In certainembodiments, provided is a compound of formula Id:

where Y, n, m, p, R¹, R², R³ and R¹⁴ are as defined herein. In certainembodiments, provided is a compound of formula Ie:

where Y, n, m, p, R¹, R², R³ and R¹⁴ are as defined herein. In certainembodiments, provided is a compound of formula If:

where Y, n, m, p, R¹, R², R³ and R¹⁴ are as defined herein. In certainembodiments, provided is a compound of formula Ig:

where Y, n, m, R¹, R², and R³ are as defined herein. In certainembodiments, provided is a compound of formula Ih: (R³)

where Y, n, m, R¹, R², and R³ are as defined herein. In certainembodiments, provided is a compound of formula Ii:

where Y, n, m, R¹, R², and R³ are as defined herein. In certainembodiments, provided is a compound of formula Ij:

where Y, n, m, R¹, R², and R³ are as defined herein. In certainembodiments, provided is a compound of formula Ik:

where Y, n, m, R¹, R², R³ and are as defined herein. In certainembodiments, provided is a compound of formula Il:

where Y, n, m, R¹, R², and R³ are as defined herein.

In certain embodiments, n is 1. In certain embodiments, provided is acompound of formula IIa:

where Y, m, R¹, R², and R³ are as defined herein. In certainembodiments, provided is a compound of formula IIb:

where Y, m, R¹, R², and R³ are as defined herein.

In certain embodiments, n is 2. In certain embodiments, provided is acompound of formula IIc:

where Y, m, R¹, R², and R³ are as defined herein. In certainembodiments, provided is a compound of formula IId:

where Y, m, R¹, R², and R³ are as defined herein. In certainembodiments, provided is a compound of formula IIe:

where Y, m, R¹, R², and R³ are as defined herein. In certainembodiments, provided is a compound of formula IIf:

where Y, m, R¹, R², and R³ are as defined herein.

In certain embodiments, n is 2. In certain embodiments, provided is acompound of formula IIg:

where Y, m, R¹, R², and R³ are as defined herein. In certainembodiments, provided is a compound of formula IIh:

where Y, m, R¹, R², and R³ are as defined herein.

In certain embodiments, n is 2. In certain embodiments, provided is acompound of formula IIi:

where Y, m, R¹, R², and R³ are as defined herein. In certainembodiments, provided is a compound of formula IIj:

where Y, m, R¹, R², and R³ are as defined herein. In certainembodiments, provided is a compound of formula IIk:

where Y, m, R¹, R², and R³ are as defined herein. In certainembodiments, provided is a compound of formula IIl:

where Y, m, R¹, R², and R³ are as defined herein.

In certain embodiments, Y is N. In certain embodiments, provided is acompound of formula IIIa:

where m, R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula IIIb:

where m, R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula IIIc:

where m, R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula IIId:

where m, R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula IIIe:

where m, R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula IIIf:

where m, R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula IIIg:

where m, R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula IIIh:

where m, R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula IIIi:

where m, R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula IIIj:

where m, R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula IIIk:

where m, R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula IIl:

where m, R¹, R², and R³ are as defined herein.

In certain embodiments, Y is CH. In certain embodiments, provided is acompound of formula IVa:

where m, R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula IVb:

where m, R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula IVc:

where m, R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula IVd:

where m, R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula IVe:

where m, R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula IVf:

where m, R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula IVg:

where m, R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula IVh:

where m, R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula IVi:

where m, R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula IVj:

where m, R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula IVk:

where m, R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula IVl:

where m, R¹, R², and R³ are as defined herein.

In certain embodiments, m is 0. In certain embodiments, m is 1, 2 or 3.In certain embodiments, m is 1. In certain embodiments, m is 2. Incertain embodiments, m is 3.

In certain embodiments, provided is a compound of formula Va, Vb or Vc:

where R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula VIa, VIb, VIc or VId:

where R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula VIIa, VIIb, VIIc, VIId, VIIe or VIIf:

where R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula VIIIa, VIIIb, VIIIc, VIIId, VIIIe orVIIIf:

where R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula IXa, IXb or IXc:

where R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula Xa, Xb, Xc or Xd:

where R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula XIa XIb, XIc, XId, XIe or XIf:

where R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula XIIa, XIIb, XIIc, XIId, XIIe or XIIf:

where R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula XIIIa, XIIIb or XIIIc:

where R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula XIVa, XIVb, XIVc or XIVd:

where R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula XVa, XVb, XVc, XVd or XVe:

where R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula XVIa, XVIb, XVIc, XVId, XVIe or XVIf:

where R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula XVIIa, XVIIb or XVIIc:

where R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula XVIIIa, XVIIIb, XVIIIc or XVIIId:

where R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula XIXa, XIXb, XIXc, XIXd or XIXe:

where R¹, R², and R³ are as defined herein. In certain embodiments,provided is a compound of formula XXa, XXb, XXc, XXd, XXe or XXf:

where R¹, R², and R³ are as defined herein.

In certain embodiments, in any of the formulas described herein, each ofR¹ and R² are independently hydrogen, deuterium, halo, C₁₋₁₂ alkyl,C₃₋₁₀ cycloalkyl, heterocyclyl, heteroaryl or aryl; wherein each C₁₋₁₂alkyl, C₃₋₁₀ cycloalkyl, heterocyclyl, heteroaryl and aryl group isoptionally substituted with one, two, three or four Z¹.

In certain embodiments, in any of the formulas described herein, each ofR¹ and R² are independently hydrogen, deuterium or C₁₋₁₂ alkyl, whichC₁₋₁₂ alkyl is optionally substituted with one, two, three or four Z¹.In certain embodiments, in any of the formulas described herein, each ofR¹ and R² are independently hydrogen, deuterium, C₁₋₁₂ haloalkyl orC₁₋₁₂ alkyl. In certain embodiments, in any of the formulas describedherein, each of R¹ and R² are independently hydrogen, deuterium or C₁₋₁₂alkyl. In certain embodiments, in any of the formulas described herein,at least one of R¹ and R² is other than hydrogen or deuterium. Incertain embodiments, in any of the formulas described herein, each of R¹and R² are independently C₁₋₁₂ haloalkyl or C₁₋₁₂ alkyl. In certainembodiments, in any of the formulas described herein, each of R¹ and R²are independently C₁₋₁₂ alkyl. In certain embodiments, in any of theformulas described herein, one of R¹ and R² is methyl and the other ofR¹ and R² is ethyl. In certain embodiments, in any of the formulasdescribed herein, R¹ and R² are methyl.

In certain embodiments, in any of the formulas described herein, R¹ is—C(R^(1a))(R^(1b))(R^(1c)), wherein each of R^(1a), R^(1b) and R^(1c) isindependently deuterium, halo, hydroxy, cyano, nitro, azido, C₁₋₁₂alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂ alkoxy, C₁₋₁₂ haloalkyl,C₁₋₁₂ haloalkoxy, C₃₋₁₀ cycloalkyl, heterocyclyl, aryl, heteroaryl,—C(═O)R¹¹, —C(═O)OR¹¹, —OC(═O)OR¹¹, —OC(═O)R¹¹, —C(═O)NR¹¹R¹²,—OC(═O)NR¹¹R¹², —NR¹¹C(═O)NR¹²R¹³, —S(═O)₁₋₂R¹¹, —S(═O)₁₋₂OR¹¹,—S(═O)₁₋₂NR¹¹, —NR¹¹S(═O), ₂R¹², —NR¹¹S(═O)₁₋₂NR¹²R¹³, —NR¹¹R¹²,—NRC(═O)R¹² or —NRC(═O)OR¹²; wherein each C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl,C₂₋₁₂ alkynyl, C₁₋₁₂ alkoxy, C₁₋₁₂ haloalkyl, C₁₋₁₂ haloalkoxy, C₃₋₁₀cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substitutedwith one, two or three Z⁷;

Z¹ is deuterium, halo, hydroxy, cyano, amino, nitro, azido, oxo, C₁₋₁₂alkyl, C₁₋₁₂ alkoxy, C₁₋₁₂ haloalkyl, C₁₋₂ haloalkoxy, C₂₋₁₂ alkenyl,C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl, heterocyclyl, aryl or heteroaryl; and

R¹¹, R¹² and R³ are as defined herein.

In certain embodiments, in any of the formulas described herein, m is 1or 3. In certain embodiments, in any of the formulas described herein, mis 1 or 2. In certain embodiments, in any of the formulas describedherein, R³ in each instance is independently deuterium, halo, hydroxy,cyano, nitro or C₁₋₁₂ alkyl, which C₁₋₁₂ alkyl is optionally substitutedwith one, two, three or four Z³. In certain embodiments, in any of theformulas described herein, m is 1 or 2, and R³ in each instance isindependently deuterium, halo, hydroxy, cyano, nitro or C₁₋₁₂ alkyl.

In certain embodiments, in any of the formulas described herein, R³ ineach instance is independently halo, hydroxy or cyano. In certainembodiments, in any of the formulas described herein, R³ in eachinstance is independently halo or cyano. In certain embodiments, in anyof the formulas described herein, R³ in each instance is independentlyfluoro or cyano.

In certain embodiments, in any of the formulas described herein, each ofR¹ and R² are independently hydrogen, deuterium or C₁₋₁₂ alkyl, whichC₁₋₁₂ alkyl is optionally substituted with one, two, three or four Z¹;and R³ in each instance is independently halo or cyano.

In certain embodiments, in any of the formulas described herein, each ofR¹ and R² are independently C₁₋₁₂ alkyl; and R³ in each instance isindependently halo or cyano.

In certain embodiments, in any of the formulas described herein, one ofR¹ and R² is methyl and the other of R¹ and R² is ethyl; and R³ in eachinstance is independently halo or cyano. In certain embodiments, in anyof the formulas described herein, one of R¹ and R² is methyl and theother of R¹ and R² is ethyl; and R³ in each instance is independentlyfluoro or cyano.

In certain embodiments, in any of the formulas described herein, R¹ andR² are methyl; and R³ in each instance is independently halo or cyano.In certain embodiments, in any of the formulas described herein, R¹ andR² are methyl; and R³ in each instance is independently fluoro or cyano.

In certain embodiments, the compound is selected from Table 1. Alsoincluded within the disclosure are stereoisomers and mixtures ofstereoisomers thereof.

TABLE 1

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

In certain embodiments, the compound is a compound selected from Table2.

TABLE 2

In certain embodiments, the compound of any Formula provided herein isprovided in the form of a pharmaceutically acceptable salt. Exemplarysalts for this purpose are described herein.

In certain embodiments, the disclosure provides a prodrug which convertsto a compound of any Formula provided herein in vivo. Exemplary prodrugsfor this purpose are known in the art and described herein.

Enantiomerically enriched compositions of the compounds disclosed hereinare also provided. In certain embodiments, the enantiomeric ratio of thecomposition is greater than 50:50. In certain embodiments, theenantiomeric ratio is calculated only with respect to a singlestereocenter (e.g., the optionally substituted phenyl moiety) withoutregard to other stereocenters which may be present on the molecule. Incertain embodiments, the composition comprises a single enantiomer ofthe compound and is substantially free (i.e., having less than or about40%, 30%, 25%, 20%, 15%, 10%, 5%, 1%, 0.05%, or 0.01%) of the otherenantiomer (or diastereomers).

3. General Synthesis

Also provided herein are methods for preparing a compound any ofFormulas I-XX, or subformula thereof. In certain embodiments, providedis a method of preparing a compound of Formula I, comprising contactinga compound of Formula C:

with a suitable hydride reagent, under conditions to provide thecompound of Formula I, wherein A, Y, n, m, p, R¹, R², R³ and R¹⁴ are asdefined herein and LG is a leaving group.

In certain embodiments, the compound of Formula C is represented byFormula C-1:

The following General Reaction Scheme I further illustrates a method ofmaking compounds of Formula I. Other methods for preparing compounds ofFormula I and related intermediates are provided in the Examples and/orknown in the art. It is understood that one skilled in the art may beable to make these compounds by similar methods or by combining othermethods known to one skilled in the art. In general, starting componentsand reagents may be obtained from sources such as Sigma Aldrich,Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI andFluorochem USA, etc. or synthesized according to sources known to thoseskilled in the art (see, for example, Advanced Organic Chemistry:Reactions, Mechanisms and Structure, 5th edition (Wiley, December 2000))or prepared as described in this disclosure.

Referring to Scheme I, compounds of Formula I, wherein A, Y, n, m, p,R¹, R², R³ and R¹⁴ are as defined herein and LG is a leaving group(e.g., halo), may be prepared by contacting compound C with a suitablehydride reagent (e.g., sodium cyanoborohydride, lithiumtriethylborohydride, etc.). Compound C can be prepared by first reactingcompound A with oxalyl chloride, and then adding the resulting solutionto compound B.

Appropriate compounds A or B can be prepared according to the morespecific methods described in the Examples which follow or by methodsknown to one of skill in the art.

When enantiomerically pure or enriched compounds are desired, chiralchromatography and/or enantiomerically pure or enriched startingmaterials (e.g., compound B) may be used as described in the Examples.It will also be appreciated by those skilled in the art that in theprocess described herein the functional groups of intermediate compoundsmay need to be protected by suitable protecting groups.

Such functional groups include hydroxy, amino, mercapto and carboxylicacid. Suitable protecting groups for hydroxy include trialkylsilyl ordiarylalkylsilyl (for example, t-butyldimethylsilyl,t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl andthe like. Suitable protecting groups for amino, amidino and guanidinoinclude t-butoxycarbonyl, benzyloxycarbonyl and the like. Suitableprotecting groups for mercapto include —C(O)—R″ (where R″ is alkyl, arylor arylalkyl), p-methoxybenzyl, trityl and the like. Suitable protectinggroups for carboxylic acid include alkyl, aryl or arylalkyl esters.Protecting groups may be added or removed in accordance with standardtechniques, which are known to one skilled in the art and as describedherein. The use of protecting groups is described in detail in Green, T.W. and P. G. M. Wutz, Protective Groups in Organic Synthesis (1999), 3rdEd., Wiley. As one of skill in the art would appreciate, the protectinggroup may also be a polymer resin such as a Wang resin, Rink resin or a2-chlorotrityl-chloride resin.

It will also be appreciated by those skilled in the art, although suchprotected derivatives of compounds of this disclosure may not possesspharmacological activity as such, they may be administered to a mammaland thereafter metabolized in the body to form compounds of thedisclosure which are pharmacologically active. Such derivatives maytherefore be described as “prodrugs.” All prodrugs of compounds of thisdisclosure are included within the scope of the disclosure. Further, theabove general scheme can be applied to any other Formula or compound asdescribed herein.

Furthermore, all compounds of Formula I or any other Formula or compoundas described herein (e.g., any of Formulas I-XX, or subformula thereof)which exist in free base or acid form can be converted to theirpharmaceutically acceptable salts by treatment with the appropriateinorganic or organic base or acid by methods known to one skilled in theart. Salts of the compounds of the disclosure can be converted to theirfree base or acid form by standard techniques.

4. Methods of Treatment

“Treatment” or “treating” is an approach for obtaining beneficial ordesired results including clinical results. Beneficial or desiredclinical results may include one or more of the following: a) inhibitingthe disease or condition (e.g., decreasing one or more symptomsresulting from the disease or condition and/or diminishing the extent ofthe disease or condition); b) slowing or arresting the development ofone or more clinical symptoms associated with the disease or condition(e.g., stabilizing the disease or condition, preventing or delaying theworsening or progression of the disease or condition and/or preventingor delaying the spread (e.g., metastasis) of the disease or condition);and/or c) relieving the disease, that is, causing the regression ofclinical symptoms (e.g., ameliorating the disease state, providingpartial or total remission of the disease or condition, enhancing effectof another medication, delaying the progression of the disease,increasing the quality of life and/or prolonging survival).

“Prevention” or “preventing” means any treatment of a disease orcondition that causes the clinical symptoms of the disease or conditionnot to develop. Compounds may, in certain embodiments, be administeredto a subject (including a human) who is at risk or has a family historyof the disease or condition.

“Subject” refers to an animal, such as a mammal (including a human),that has been or will be the object of treatment, observation orexperiment. The methods described herein may be useful in human therapyand/or veterinary applications. In certain embodiments, the subject is amammal. In certain embodiments, the subject is a human.

The term “therapeutically effective amount” or “effective amount” of acompound described herein or a pharmaceutically acceptable salt,prodrug, stereoisomer or a mixture of stereoisomers thereof means anamount sufficient to effect treatment when administered to a subject, toprovide a therapeutic benefit such as amelioration of symptoms orslowing of disease progression. For example, a therapeutically effectiveamount may be an amount sufficient to decrease a symptom of a disease orcondition of as described herein. The therapeutically effective amountmay vary depending on the subject and disease or condition beingtreated, the weight and age of the subject, the severity of the diseaseor condition and the manner of administering, which can readily bedetermined by one of ordinary skill in the art.

The term “trauma” as used herein refers to any physical damage to thebody caused by violence, accident, fracture etc. The term “ischemia”refers to a cardiovascular disorder characterized by a low oxygen stateusually due to the obstruction of the arterial blood supply orinadequate blood flow leading to hypoxia in the tissue. The term“stroke” refers to cardiovascular disorders caused by a blood clot orbleeding in the brain, most commonly caused by an interruption in theflow of blood in the brain as from clot blocking a blood vessel and incertain embodiments of the disclosure the term stroke refers to ischemicstroke or hemorrhagic stroke. The term “myocardial infarction” refers toa cardiovascular disorder characterized by localized necrosis resultingfrom obstruction of the blood supply.

The methods described herein may be applied to cell populations in vivoor ex vivo. “In vivo” means within a living individual, as within ananimal or human. In this context, the methods described herein may beused therapeutically in an individual. “Ex vivo” means outside of aliving individual. Examples of ex vivo cell populations include in vitrocell cultures and biological samples including fluid or tissue samplesobtained from individuals. Such samples may be obtained by methods wellknown in the art. Exemplary biological fluid samples include blood,cerebrospinal fluid, urine and saliva. In this context, the compoundsand compositions described herein may be used for a variety of purposes,including therapeutic and experimental purposes. For example, thecompounds and compositions described herein may be used ex vivo todetermine the optimal schedule and/or dosing of administration of acompound of the present disclosure for a given indication, cell type,individual and other parameters. Information gleaned from such use maybe used for experimental purposes or in the clinic to set protocols forin vivo treatment. Other ex vivo uses for which the compounds andcompositions described herein may be suited are described below or willbecome apparent to those skilled in the art. The selected compounds maybe further characterized to examine the safety or tolerance dosage inhuman or non-human subjects. Such properties may be examined usingcommonly known methods to those skilled in the art.

Experiments with knockout animal models and Necrostatin 1, a receptorinteracting protein kinase 1 inhibitor, have demonstrated theeffectiveness of receptor interacting protein kinase 1 inhibition inprotecting tissues from inflammatory bowel diseases (e.g., ulcerativecolitis and Crohn's disease), psoriasis, retinal-detachment-inducedphotoreceptor necrosis, retinitis pigmentosa, cerulein-induced acutepancreatits and sepsis/systemic inflammatory response syndrome (SIRS)and alleviating ischemic brain injury, retinal ischemia/reperfusioninjury, Huntington's disease, renal ischemia reperfusion injury,cisplatin induced kidney injury, traumatic brain injury, hematologicaland solid organ malignancies, bacterial infections and viral infections(e.g., tuberculosis and influenza) and lysosomal storage diseases.

The receptor interacting protein kinase 1 inhibitors of the presentdisclosure are therefore useful for treating diseases and conditionsmediated by receptor interacting protein kinase 1, including but notlimited to inflammatory diseases or disorders, necrotic cell diseases,neurodegenerative diseases, central nerve system (CNS) diseases, oculardiseases, infections and malignancies. In certain embodiments, thereceptor interacting protein kinase 1 inhibitors described herein caninhibit inflammation, protect tissue or cell from damage or undesiredcell death (e.g., necrosis or apoptosis), ameliorate symptoms andimprove immune response in a patient suffering from any of theprescribed diseases or conditions. Moreover, the compounds may besuitable for treatment of immune-mediated disease, such as but notlimited to, allergic diseases, autoimmune diseases and prevention oftransplant rejection.

Necrotic Cell Diseases

The compounds described herein may be used for the treatment ofdiseases/disorders caused or otherwise associated with cellularnecrosis. In particular, the disclosure provides methods for preventingor treating a disorder associated with cellular necrosis in a mammal,comprising the step of administering to said mammal a therapeuticallyeffective amount of a compound or composition described herein. The term“necrotic cell disease” refers to diseases associated with or caused bycellular necrosis, for example trauma, ischemia, stroke, cardiacinfarction, infection, Gaucher's disease, Krabbe disease, sepsis,Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis,Huntington's disease, HIV-associated dementia, retinal degenerativedisease, glaucoma, age-related macular degeneration, rheumatoidarthritis, psoriasis, psoriatic arthritis or inflammatory bowel disease.

The necrotic cell diseases can be acute diseases such as trauma,ischemia, stroke, cardiac infarction, anthrax lethal toxin inducedseptic shock, sepsis, cell death induced by LPS and HIV induced T-celldeath leading to immunodeficiency. In certain embodiments the disorderis an ischemic disease of organs including but not limited to brain,heart, kidney and liver.

The necrotic cell diseases also include chronic neurodegenerativediseases, such as Parkinson's disease, Huntington's disease, amyotrophiclateral sclerosis, Alzheimer's disease, infectious encephalopathy,dementia such as HIV associated dementia.

In some different embodiments, the disorder is an ocular disorder suchas retinal degenerative disease, glaucoma or age-related maculardegeneration. In some different embodiments, the disorder is a centralnervous system (CNS) disorder.

Inflammatory Diseases or Disorders

The receptor interacting protein kinase 1 inhibitors described hereinmay be used to treat inflammatory diseases and disorders. Inflammatorydiseases and disorders typically exhibit high levels of inflammation inthe connective tissues or degeneration of these tissues.

Non-limiting examples of inflammatory diseases and disorders includeAlzheimer's disease, ankylosing spondylitis, arthritis includingosteoarthritis, rheumatoid arthritis (RA), psoriasis, asthma,atherosclerosis, Crohn's disease, colitis, dermatitis, diverticulitis,fibromyalgia, hepatitis, irritable bowel syndrome (IBS), inflammatorybowel disease (IBD), systemic lupus erythematous (SLE), nephritis,Parkinson's disease and ulcerative colitis. In certain embodiments, thecompounds and compositions of the present disclosure are useful fortreating an autoimmune disorder, such as rheumatoid arthritis,psoriasis, psoriatic arthritis, encephalitis, allograft rejection,autoimmune thyroid diseases (such as Graves' disease and Hashimoto'sthyroiditis), autoimmune uveoretinitis, giant cell arteritis,inflammatory bowel diseases (including Crohn's disease, ulcerativecolitis, regional enteritis, granulomatous enteritis, distal ileitis,regional ileitis, and terminal ileitis), insulin-dependent diabetesmellitus, multiple sclerosis, pernicious anemia, sarcoidosis,scleroderma, and systemic lupus erythematosus. In an embodiment, thereceptor interacting protein kinase 1 inhibitors described herein areuseful for treating autoimmune encephalitis.

In certain embodiments, the compounds and compositions are useful fortreating rheumatoid arthritis (RA). In certain embodiments, thecompounds and compositions are useful for treating ulcerative colitis.In certain embodiments, the compounds and compositions are useful fortreating psoriasis.

In certain embodiments, the disorder is an inflammatory disease of theintestines such as Crohn's disease or ulcerative colitis (both generallyknown together as inflammatory bowel disease). In certain embodiments,the mammal is a primate, canine or feline subject. In certainembodiments, the mammal is a human subject. While not wishing to bebound by theory, it is believed that inhibition of receptor interactingprotein kinase 1 by the presently disclosed compounds is responsible, atleast in part, for their anti-inflammatory activity. Accordingly,embodiments of the disclosure also include methods for inhibitingreceptor interacting protein kinase 1, either in vitro or in a subjectin need thereof, the method comprises contacting a receptor interactingprotein kinase 1 with a compound disclosed herein. In some of theseembodiments, inhibiting receptor interacting protein kinase 1 iseffective to block (partially or fully) the release of inflammatorymediators such as TNF and/or IL6.

Ocular Conditions

The receptor interacting protein kinase 1 inhibitors described hereincan also be used to treat ocular conditions, for example to reduce orprevent the loss of photoreceptor and/or retinal pigment epithelial cellviability.

In one aspect, the disclosure provides a method of preserving the visualfunction of an eye of a subject with an ocular condition, wherein asymptom of the ocular condition is the loss of photoreceptor cellviability in the retina of the eye with the condition. The methodcomprises administering to the eye of the subject an effective amount ofa compound or composition described herein, thereby preserving theviability of the photoreceptor cells disposed within the retina of theeye. After administration, the visual function (e.g., visual acuity) ofthe eye may be preserved or improved relative to the visual function ofthe eye prior to administration.

The ocular condition may be a condition selected from the groupconsisting of age-related macular degeneration (AMD), retinosispigmentosa (RP), macular edema, diabetic retinopathy, central areolarchoroidal dystrophy, BEST disease, adult vitelliform disease, patterndystrophy, myopic degeneration, central serous retinopathy, Stargardt'sdisease, Cone-Rod dystrophy, North Carolina dystrophy, infectiousretinitis, inflammatory retinitis, uveitis, toxic retinitis andlight-induced toxicity. AMD may be the neovascular or the dry form ofAMD. Retinal detachment may be a rhegmatogenous, a serous or atractional retinal detachment.

In another aspect, the disclosure provides a method of preserving theviability of retinal pigment epithelial (RPE) cells within the retina ofa subject with an ocular condition, wherein a symptom of the ocularcondition is the loss of retinal pigment epithelial cells in the retinaof the eye with the condition. The method comprises administering to theeye of the subject an effective amount of a compound or compositiondescribed herein, thereby preserving the viability of the retinalpigment epithelial cells. The ocular condition may be selected from thegroup consisting of AMD, BEST disease, myopic degeneration, Stargardt'sdisease, uveitis, adult foveomacular dystrophy, fundus falvimaculatus,multiple evanescent white dot syndrome, serpiginous choroidopathy, acutemultifocal posterior placoid epitheliopathy (AMPPE) and other uveitisdisorders.

The ocular condition may be a condition selected from the groupconsisting of age-related macular degeneration (AMD), retinosispigmentosa (RP), macular edema, diabetic retinopathy, central areolarchoroidal dystrophy, BEST disease, adult vitelliform disease, patterndystrophy, myopic degeneration, central serous retinopathy, Stargardt'sdisease, Cone-Rod dystrophy, North Carolina dystrophy, infectiousretinitis, inflammatory retinitis, uveitis, toxic retinitis andlight-induced toxicity. Therefore, in certain embodiments, the methodcomprises administering to the eye an effective amount of a compound orcomposition described herein, thereby preserving the viability of thephotoreceptor cells disposed within the retina of the subject with acondition.

In another aspect, the disclosure provides a method of preserving theviability of photoreceptor cells disposed within a retina of a mammalianeye following retinal detachment. The method comprises administering acompound or composition described herein to the eye in which a region ofthe retina has been detached in amounts sufficient to preserve theviability of photoreceptor cells disposed within the region of thedetached retina.

In certain embodiments, the retinal detachment may be a rhegmatogenousretinal detachment, tractional retinal detachment or serous retinaldetachment. In certain embodiments, the retinal detachment may occur asa result of a retinal tear, retinoblastoma, melanoma or other cancers,diabetic retinopathy, uveitis, choroidal neovascularization, retinalischemia, pathologic myopia or trauma.

In another aspect, the disclosure provides a method of preserving visualfunction of an eye of a subject with an ocular condition selected fromthe group consisting of AMD, RP, macular edema, central areolarchoroidal dystrophy, retinal detachment, diabetic retinopathy, BESTdisease, adult vitelliform disease, pattern dystrophy, myopicdegeneration, central serous retinopathy, Stargardt's disease, Cone-Roddystrophy, North Carolina dystrophy, infectious retinitis, inflammatoryretinitis, uveitis, toxic retinitis and light-induced toxicity, whereina symptom of the ocular condition is the loss of photoreceptor cellsviability in the retina of the eye, wherein the method comprisestreating the subject with a compound or composition described herein tothe subject.

In another aspect, the disclosure provides a method of preserving thevisual function of an eye of a subject with an ocular condition, whereina symptom of the ocular condition is the loss of photoreceptor cellviability and/or RPE viability in the retina of the eye wherein themethod comprises treating the subject with a compound or compositiondescribed herein to the subject.

In certain embodiments is provided a method of preserving the visualfunction of an eye of a subject with ocular conditions, wherein asymptom of the ocular condition is the loss of retinal ganglion cellviability in the retina of the eye with the conditions. The methodcomprises administering to the eye of the subject an effective amount ofa compound or composition, thereby preserving the viability of theretinal ganglion cells disposed within the retina of the eye. Afteradministration of the compound or composition, the visual function ofthe eye may be preserved or improved relative to the visual function ofthe eye prior to administration. Further, after the administration, thepreserved retinal ganglion cell is capable of supporting axonalregeneration.

In each of the foregoing methods, the ocular condition, wherein asymptom of the condition is the loss of retinal ganglion cell viabilityin the retina of the eye, includes but is not limited to glaucoma, opticnerve injury, optic neuritis, optic neuropathies, diabetic retinopathy,central retinal artery occlusion and central retinal vein occlusion. Itis contemplated that the forgoing methods may be used for the treatmentof optic neuropathies such as ischemic optic neuropathy (e.g., arteriticor non-arteritic anterior ischemic neuropathy and posterior ischemicoptic neuropathy), compressive optic neuropathy, infiltrative opticneuropathy, traumatic optic neuropathy, mitochondrial optic neuropathy(e.g., Leber's optic neuropathy), nutritional optic neuropathy, toxicoptic neuropathy and hereditary optic neuropathy (e.g., Leber's opticneuropathy, Dominant Optic Atrophy, Behr's syndrome).

Also disclosed is a method of preserving the visual function of an eyeof a subject with an ocular condition selected from the group consistingof glaucoma, optic nerve injury, optic neuropathies, diabeticretinopathy, central retinal artery occlusion and central retinal veinocclusion. The method comprises administering to the eye of the subjectan effective amount of a compound or composition described herein,thereby preserving the viability of the retinal ganglion cells disposedwithin the retina of the eye and the visual function of the eye.

In another aspect, disclosed herein is a method of preserving theviability of retinal ganglion cells disposed within a retina of amammalian eye affected by, for example, glaucoma, optic nerve injury,optic neuritis, optic neuropathies, diabetic retinopathy, centralretinal artery occlusion and central retinal vein occlusion. The methodcomprises administering a compound or composition described herein tothe eye in which a region of the retina has been affected in amountssufficient to preserve the viability of retinal ganglion cells disposedwithin the region of the affected retina. The preserved retinal ganglioncell is capable of supporting axonal regeneration.

Also disclosed is a method for promoting axon regeneration in an eye ofa subject with an ocular condition, wherein a symptom of the ocularcondition is the loss of retinal ganglion cell viability in the retinaof the eye with the condition. The method comprises administering to theeye of the subject an effective amount of a compound or compositiondescribed herein, thereby promoting axon regeneration of the retinalganglion cell within the retina of the eye.

In each of the foregoing embodiments, it is understood that the methodsand compositions described herein can be used to preserve the viabilityand/or promote axon regeneration of retinal ganglion cells duringtreatment of the underlying conditions including, but not limited to,glaucoma, optic nerve injury, optic neuritis, optic neuropathies,diabetic retinopathy, central retinal artery occlusion and centralretinal vein occlusion.

Neurodegenerative and CNS Diseases

The receptor interacting protein kinase 1 inhibitors described hereinmay also be used to treat neurodegenerative diseases. Neurodegenerativediseases can affect many of the body's activities, such as balance,movement, talking, breathing and heart function. Neurodegenerativediseases can be genetic or caused by medical conditions such asalcoholism, tumors, strokes, toxins, chemicals and viruses.

Non-limiting examples of neurodegenerative diseases and CNS diseasesinclude Niemann-Pick disease, type C1 (NPC1), Alzheimer's disease,amyotrophic lateral sclerosis (ALS), Friedreich's ataxia, Huntington'sdisease, Lewy body disease, Parkinson's disease and spinal muscularatrophy.

In an embodiment, the receptor interacting protein kinase 1 inhibitorsdescribed herein may be used to treat NPC1 via inhibiting necroptosisthat causes neuronal loss. In certain embodiments, the compounds andcompositions of the present disclosure are useful for treatingAlzheimer's disease. In certain embodiments, the compounds andcompositions of the present disclosure are useful for treatingParkinson's disease. In certain embodiments, the compounds andcompositions of the present disclosure are useful for treatingamyotrophic lateral sclerosis (ALS).

More generally, the receptor interacting protein kinase 1 inhibitorsdescribed herein can be used to preserve neuron viability and promoteaxon growth and nerve functions within the central nervous system (CNS).Accordingly, the compounds may be used to reduce or even reverse theloss of cognitive, motor and sensory functions associated with a CNSdisease or disorder, by preserving neuron viability and/or promotingaxon regeneration and/or nerve functions.

The receptor interacting protein kinase 1 inhibitors described hereincan be used in a method for promoting axon regeneration in a CNS neuron,such as a CNS sensory neuron, a motor neuron, a cortical neuron, acerebellar neuron, a hippocampal neuron and a midbrain neuron. Thereceptor interacting protein kinase 1 inhibitors described herein can beused in a method for promoting nerve function or preserving theviability following injury to a CNS neuron. In certain embodiments,these compounds can be used to promote regeneration of an axon in a CNSneuron that is degenerated in the CNS disease or disorder. The receptorinteracting protein kinase 1 inhibitors may be administered by anyconventional means, such as locally to the neuron or applied ex vivobefore re-implantation.

Accordingly, in one aspect, the disclosure provides a method of treatinga CNS disorder in a subject in need thereof, wherein a symptom of theCNS disorder is axon degeneration or injury within a CNS neuron. Themethod comprises administering to the subject an effective amount of acompound or composition disclosed herein thereby to promote regenerationof an axon in a CNS neuron affected by the CNS disorder. Followingadministration, neural functions may be measured, for example, as anindication of axon regeneration. It is also contemplated that, followingadministration of the compound or composition, the neuron function ofthe CNS neuron is preserved or improved relative to the neuron functionprior to administration.

The CNS disorder includes, but is not limited to, brain injury, spinalcord injury, dementia, stroke, Alzheimer's disease, amyotrophic lateralsclerosis (ALS/Lou Gehrig's Disease), Parkinson's disease, Huntington'sdisease, multiple sclerosis, diabetic neuropathy, polyglutamine (polyQ)diseases, stroke, Fahr disease, Menke's disease, Wilson's disease,cerebral ischemia and a prion disorder. In exemplary embodiments, theCNS disorder is brain injury or spinal cord injury.

Also provided herein are methods for promoting neuron survival and axonregeneration in the CNS. CNS disorders characterized by impaired orfailing axon growth or axon degeneration may arise from CNS neuroninjury (e.g., trauma, surgery, nerve compression, nerve contusion, nervetransection, neurotoxicity or other physical injury to the brain orspinal cord) or neurodegenerative CNS disease, wherein a symptom of thedisorder is axon degeneration (e.g., Alzheimer's disease, amyotrophiclateral sclerosis (ALS/Lou Gehrig's Disease), Parkinson's disease,multiple sclerosis, diabetic neuropathy, polyglutamine (polyQ) diseases,stroke, Fahr disease, Menke's disease, Wilson's disease, cerebralischemia, prion disorder (e.g., Creutzfeldt-Jakob disease). In certainembodiments, the CNS disorder is brain injury (e.g., traumatic braininjury) or spinal cord injury (e.g., chronic, acute or traumatic spinalcord injury). In certain embodiments, the CNS disorder affects asubject's basic vital life functions such as breathing, heart beat andblood pressure, e.g., an injury to or aneurysm in the brain stem.

In certain embodiments, the CNS disorder affects a subject's cognitiveability, such as, brain injury to the cerebral cortex or aneurodegenerative CNS disorder, such as, Alzheimer's disease,frontotemporal dementia, dementia with Lewy bodies, corticobasaldegeneration, progressive supranuclear palsy and prion disorders.

In certain embodiments, the CNS disorder affects a subject's movementand/or strength, such as injury to the brain or spinal cord or aneurodegenerative CNS disorder such as Parkinson's disease,frontotemporal dementia, dementia with Lewy bodies, corticobasaldegeneration, progress supranuclear palsy, Huntington's disease,multiple system atrophy, amyotrophic lateral sclerosis and hereditaryspastic paresis.

In certain embodiments, the CNS disorder affects a subject'scoordination, such as brain injury to the cerebellum or aneurodegenerative CNS disorder such as spinocerebellar atrophies,Friedreich's ataxia and prion disorders.

In each of the foregoing methods, the CNS disorder includes, but is notlimited to, brain injury, spinal cord injury, Alzheimer's disease,amyotrophic lateral sclerosis (ALS/Lou Gehrig's Disease), Parkinson'sdisease, multiple sclerosis, diabetic neuropathy, polyglutamine (polyQ)diseases, stroke, Fahr disease, Menke's disease, Wilson's disease,cerebral ischemia, a prion disorder (e.g., Creutzfeldt-Jakob disease),dementia (e.g., frontotemporal dementia, dementia with Lewy bodies),corticobasal degeneration, progressive supranuclear palsy, multiplesystem atrophy, hereditary spastic paraparesis and spinocerebellaratrophies.

Tissue Injuries or Damages

The ability of the compounds described herein to inhibit inflammationand cell death makes them suitable for ameliorating tissue injuries ordamages. The tissue injuries or damages may be a result of any of thediseases or conditions described above. For example, the compounds maybe used for amelioration of brain tissue injury or damage followingischemic brain injury or traumatic brain injury or for amelioration ofheart tissue injury or damage following myocardial infarction or foramelioration of brain tissue injury or damage associated withHuntington's disease, Alzheimer's disease or Parkinson's disease or foramelioration of liver tissue injury or damage associated withnon-alcohol steatohepatitis, alcohol steatohepatitis, autoimmunehepatitis autoimmune hepatobiliary diseases or primary sclerosingcholangitis or for the amelioration of liver tissue injury or damageassociated with overdose of acetaminophen or for amelioration of kidneytissue injury or damage following renal transplant or the administrationof nephrotoxic drugs or substances.

Non-limiting examples of brain injury or damage include stroke (e.g.,hemorrhagic and non-hemorrhagic), traumatic brain injury (TBI), cerebralhemorrhage, subarachnoid hemorrhage, intracranial hemorrhage secondaryto cerebral arterial malformation, cerebral infarction, perinatal braininjury, non-traumatic brain injury, Alzheimer's disease, Parkinson'sdisease, Huntington's disease, multiple sclerosis, amyotrophic lateralsclerosis, brain hemorrhage, brain infections, brain tumor, subclinicalbrain injury, spinal cord injury, anoxic-ischemic brain injury, focalcerebral ischemia, global cerebral ischemia, and hypoxic hypoxia.

In an embodiment, the compounds and compositions of the presentdisclosure may be used to treat peritoneal tissue injury. Non-limitingexamples of peritoneal tissue injury include peritoneal deterioration,peritoneal sclerosis, and peritoneal cancer. For example, the receptorinteracting protein kinase 1 inhibitors described herein may be used totreat peritoneal damage caused by peritoneal dialysis fluid (PDF) andPD-related side effects.

Liver Injury and Diseases

In an embodiment, the compounds and compositions of the presentdisclosure may be used to treat liver injury and diseases. Non-limitingexamples of liver injury or damage include not only degeneration ornecrosis of liver parenchyma cells which results from injury caused by acertain factor, but also undesirable phenomena caused by biologicalreactions to the injury, such as mobilization, infiltration, activationof Kupffer cells, leukocytes and the like, fibrosis of the liver tissue,etc., which reactions occur alone or in combination. In an embodiment,the receptor interacting protein kinase 1 inhibitors described hereinmay be used to treat steatohepatitis and hepatocellular carcinoma viainhibiting receptor interacting protein kinase 1 activity-dependentapoptosis of hepatocytes and hepatocarcinogenesis. In an embodiment, thereceptor interacting protein kinase 1 inhibitors described herein may beused to treat acute cholestasis and liver injury.

Kidney Injury and Diseases

In an embodiment, the compounds and compositions of the presentdisclosure may be used to treat kidney injury and diseases. Non-limitingexamples of kidney diseases include chronic kidney disease (CKD) (e.g.,glomerular diseases, tubulointerstitial diseases, obstruction,polycystic kidney disease), acute kidney injury (AKI), diabeticnephropathy, glomerulonephritis, focal glomerulosclerosis, immunecomplex nephropathy or lupus nephritis. Kidney disease may be caused bydrug-induced renal injury or kidney graft rejection. Kidney disease maybe characterized as nephrotic syndrome or renal insufficiency. In anembodiment, the receptor interacting protein kinase 1 inhibitorsdescribed herein may be used to treat kidney diseases (e.g., AKI) viainhibiting cell death pathway in kidney diseases. In an embodiment, thereceptor interacting protein kinase 1 inhibitors described herein may beused to treat patient with kidney stones and to prevent crystal-inducedcytotoxicity and acute kidney injury via inhibiting receptor interactingprotein kinase 3-MLKL-mediated necroptosis.

Malignancies

In an embodiment, the compounds and compositions of the presentdisclosure are useful for treating malignancies/cancers such ascarcinoma, sarcoma, melanoma, lymphoma or leukemia. Non-limitingexamples of malignancies suitably treated by the receptor interactingprotein kinase 1 inhibitors described herein include lung cancer (e.g.non-small cell lung cancer, small-cell lung cancer), hepatocellularcancer, melanoma, pancreatic cancer, urological cancer, bladder cancer,colorectal cancer, colon cancer, breast cancer, prostate cancer, renalcancer, thyroid cancer, gall bladder cancer, peritoneal cancer, ovariancancer, cervical cancer, gastric cancer, endometrial cancer, esophagealcancer, head and neck cancer, neuroendocrine cancer, CNS cancer, braintumors (e.g., glioma, anaplastic oligodendroglioma, adult glioblastomamultiforme, and adult anaplastic astrocytoma), bone cancer, soft tissuesarcoma, retinoblastomas, neuroblastomas, peritoneal effusions,malignant pleural effusions, mesotheliomas, Wilms tumors, trophoblasticneoplasms, hemangiopericytomas, Kaposi's sarcomas, myxoid carcinoma,round cell carcinoma, squamous cell carcinomas, esophageal squamous cellcarcinomas, oral carcinomas, vulval cancer, cancers of the adrenalcortex, ACTH producing tumors, lymphoma, and leukemia.

Infectious Diseases

In an embodiment, the compounds and compositions of the presentdisclosure are useful for treating infectious diseases resulting fromthe presence of pathogenic agents, including pathogenic viruses,pathogenic bacteria, fungi, protozoa, multicellular parasites andaberrant proteins known as prions. Non-limiting examples of infectiousdiseases suitably treated by the receptor interacting protein kinase 1inhibitors described herein include virus infectious diseases andbacterial infectious diseases. The virus infectious disease is notparticularly limited and includes, for example, infectious diseases withrespiratory infectious viruses (e.g., infectious diseases due torespiratory infectious viruses such as influenza virus, rhino virus,corona virus, parainfluenza virus, RS virus, adeno virus, reo virus andthe like), herpes zoster caused by herpes virus, diarrhea caused byrotavirus, viral hepatitis, AIDS and the like. The bacterial infectiousdisease is not particularly limited and includes, for example,infectious diseases caused by Bacillus cereus, Vibrio parahaemolyticus,Enterohemorrhagic Escherichia coli, Staphylococcus aureus, MRSA,Salmonella, Botulinus, Candida and the like.

Bone Diseases

In an embodiment, the compounds and compositions of the presentdisclosure are useful for treating bone diseases that may result from abone remodeling disorder whereby the balance between bone formation andbone resorption is shifted. Non-limiting examples of bone remodelingdisorders include osteoporosis, Paget's disease, osteoarthritis,rheumatoid arthritis, achondroplasia, osteochodrytis,hyperparathyroidism, osteogenesis imperfecta, congenitalhypophosphatasia, fribromatous lesions, fibrous displasia, multiplemyeloma, abnormal bone turnover, osteolytic bone disease and periodontaldisease. Additional examples of bone diseases suitably treated by thereceptor interacting protein kinase 1 inhibitors described hereininclude bone fracture, bone trauma, or a bone deficit conditionassociated with post-traumatic bone surgery, post-prosthetic jointsurgery, post-plastic bone surgery, post-dental surgery, bonechemotherapy treatment or bone radiotherapy treatment. Additionalexamples of diseases affecting bone or bone joints suitably treated bythe receptor interacting protein kinase 1 inhibitors described hereininclude metastatic bone cancer, rheumatic diseases such as rheumatoidarthritis, osteoarthritis and other inflammatory arthropathies. In anembodiment, the receptor interacting protein kinase 1 inhibitorsdescribed herein may be used to treat postmenopausal osteoporosis viainhibiting osteocyte necroptosis and trabecular deterioration.

Cardiovascular Diseases

In an embodiment, the compounds and compositions of the presentdisclosure are useful for treating cardiovascular diseases that may berelate to the cardiovascular disorders of fragile plaque disorder,occlusive disorder and stenosis. Non-limiting cardiovascular diseasesinclude coronary artery disorders and peripheral arterial disorders,including, among others, atherosclerosis, arterial occlusion, aneurysmformation, thrombosis, post-traumatic aneurysm formation, restenosis,and post-operative graft occlusion. It is believed that atherosclerosisresults from maladaptive inflammation driven primarily by macrophages.Thus, the compounds and compositions of the present disclosure may beused to treat atherosclerosis via inhibiting macrophage necroptosis.

Transplantation

In an embodiment, the compounds and compositions of the presentdisclosure are useful for treating transplant patients. Non-limitingexamples of transplant patient suitably treated by the receptorinteracting protein kinase 1 inhibitors described herein includepatients with solid and non-solid organ and tissue transplantations andtransplants, such as liver, heart, kidney, and heterologous andautologous bone marrow transplantations/transplants. Typically,immunosuppressive therapy is used to avoid graft rejection in recipientsof solid organ transplants. Recipients of bone marrow transplants areusually subjected to extensive irradiation and chemotherapy prior totransplantation. It is believed that receptor interacting protein kinase1 and NF-κB signaling in dying cells determines cross-priming of CD8⁺ Tcells. Thus, the receptor interacting protein kinase 1 inhibitorsdescribed herein may be used to treat transplant patient and avoid graftrejection by modulating cross-priming of CD8⁺ T cells.

Other Diseases and Conditions

Additional examples of diseases and disorders suitably treated by thereceptor interacting protein kinase 1 inhibitors described hereininclude Gaucher disease, organ failure, pancreatitis, atopic dermatitis,spondyloarthritis, gout, systemic onset juvenile idiopathic arthritis(SoJIA), systemic lupus erythematosus (SLE), Sjogren's syndrome,systemic scleroderma, anti-phospholipid syndrome (APS), vasculitis,primary sclerosing cholangitis (PSC), acetaminophen toxicity, kidneydamage/injury (nephritis, renal transplant, surgery, administration ofnephrotoxic drugs e.g. cisplatin, acute kidney injury(AKI)), Celiacdisease, autoimmune idiopathic thrombocytopenic purpura (autoimmuneITP), cerebrovascular accident (CVA, stroke), myocardial infarction(MI), allergic diseases (including asthma), diabetes, Wegener'sgranulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1converting enzyme (ICE/caspase-1) associated fever syndrome, chronicobstructive pulmonary disease (COPD), tumor necrosis factorreceptor-associated periodic syndrome (TRAPS), peridontitis,NEMO-deficiency syndrome (F-kappa-B essential modulator gene (also knownas IKK gamma or IKKG) deficiency syndrome), HOIL-1 deficiency ((alsoknown as RBCK1) heme-oxidized IRP2 ubiquitin ligase-1 deficiency),linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome,hematological and solid organ malignancies, bacterial infections andviral infections (e.g., tuberculosis and influenza) and lysosomalstorage diseases.

Non-limiting examples of lysosomal storage diseases include Gaucherdisease, GM2 Gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria,cholesteryl ester storage disease, chronic hexosaminidase A deficiency,cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis,galactosialidosis, GM1 gangliosidosis, mucolipidosis, infantile freesialic acid storage disease, juvenile hexosaminidase A deficiency,Krabbe disease, lysosomal acid lipase deficiency, metachromaticleukodystrophy, mucopolysaccharidoses disorders, multiple sulfatasedeficiency, Niemann-Pick disease, neuronal ceroid lipofuscinoses, Pompedisease, pycnodysostosis, Sandhoff disease, Schindler disease, sialicacid storage disease, Tay-Sachs and Wolman disease.

In certain embodiments, provided are compounds and compositions for usein medicine. In certain embodiments, the compounds and compositions arefor use in the treatment of a receptor interacting protein kinase1-mediated disease or disorder. Also provided is a method of treating areceptor interacting protein kinase 1-mediated disease or disordercomprising administering a therapeutically effective amount of acompound or pharmaceutical composition disclosed herein to a subject inneed thereof.

5. Compositions

For the purposes of administration, the compounds of the presentdisclosure may be administered as a raw chemical or may be formulated aspharmaceutical compositions. Pharmaceutical compositions of the presentdisclosure comprise a compound of any of Formulas I-XX, or subformulathereof and a pharmaceutically acceptable carrier, diluent or excipient.Accordingly, different embodiments are directed to pharmaceuticalcompositions comprising any one or more of the foregoing compounds ofany of Formulas I-XX, or subformula thereof or a pharmaceuticallyacceptable salt, prodrug, stereoisomer or a mixture of stereoisomersthereof and a pharmaceutically acceptable carrier, diluent or excipientare also provided in various embodiments.

The pharmaceutical compositions of the present disclosure may bespecially formulated for administration in solid or liquid form,including those adapted for the following: oral administration, forexample, drenches (aqueous or non-aqueous solutions or suspensions),tablets, e.g., those targeted for buccal, sublingual and systemicabsorption, boluses, powders, granules, pastes for application to thetongue; parenteral administration, for example, by subcutaneous,intramuscular, intravenous or epidural injection as, for example, asterile solution or suspension or sustained-release formulation; topicalapplication, for example, as a cream, ointment or a controlled-releasepatch or spray applied to the skin; intravaginally or intrarectally, forexample, as a pessary, cream or foam; sublingually; ocularly;transdermally; or nasally, pulmonary and to other mucosal surfaces.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically-acceptable carrier” as used herein means apharmaceutically-acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient or solvent encapsulatingmaterial, involved in carrying or transporting the subject compound fromone organ or portion of the body, to another organ or portion of thebody. Each carrier must be “acceptable” in the sense of being compatiblewith the other ingredients of the formulation and not injurious to thepatient. Some examples of materials which can serve aspharmaceutically-acceptable carriers include: sugars, such as lactose,glucose and sucrose; starches, such as corn starch and potato starch;cellulose and its derivatives, such as sodium carboxymethyl cellulose,ethyl cellulose and cellulose acetate; surfactants, such as polysorbate80 (i.e., Tween 80); powdered tragacanth; malt; gelatin; talc;excipients, such as cocoa butter and suppository waxes; oils, such aspeanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, cornoil and soybean oil; glycols, such as propylene glycol; polyols, such asglycerin, sorbitol, mannitol and polyethylene glycol; esters, such asethyl oleate and ethyl laurate; agar; buffering agents, such asmagnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-freewater; isotonic saline; Ringer's solution; ethyl alcohol; pH bufferedsolutions; polyesters, polycarbonates and/or polyanhydrides; and othernon-toxic compatible substances employed in pharmaceutical formulations.Examples of such formulations include, but are not limited to DMSO, 10mM DMSO, 8% hydroxypropyl-beta-cyclodextrin in PBS, propylene glycol,etc. For example, in a certain embodiment the compounds of thedisclosure can be used as 4 mM solution in 8%hydroxypropyl-beta-cyclodextrin in PBS for parenteral administration. Inanother certain embodiments, the compounds of the disclosure can be usedas a suspension in 0.5% aqueous CMC containing 0.1% TWEEN 80.

As set out herein, certain embodiments of the present compounds maycontain a basic functional group, such as amino or methylamino (NCH₃)and are, thus, capable of forming pharmaceutically-acceptable salts withpharmaceutically-acceptable acids. The term “pharmaceutically-acceptablesalts” in this respect refers to the relatively non-toxic, inorganic andorganic acid addition salts of compounds of the present disclosure.These salts can be prepared in situ in the administration vehicle or thedosage form manufacturing process or by separately reacting a purifiedcompound of the disclosure in its free base form with a suitable organicor inorganic acid and isolating the salt thus formed during subsequentpurification. Representative salts include the hydrobromide,hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate,valerate, oleate, palmitate, stearate, laurate, benzoate, lactate,phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate,napthylate, mesylate, glucoheptonate, lactobionate and laurylsulphonatesalts and the like.

The pharmaceutically acceptable salts of the subject compounds includethe conventional nontoxic salts or quaternary ammonium salts of thecompounds, e.g., from non-toxic organic or inorganic acids. For example,such conventional nontoxic salts include those derived from inorganicacids such as hydrochloride, hydrobromic, sulfuric, sulfamic,phosphoric, nitric and the like; and the salts prepared from organicacids such as acetic, propionic, succinic, glycolic, stearic, lactic,malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicyclic, sulfanilic,2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isothionic and the like.

In other cases, the compounds of the present disclosure may contain oneor more acidic functional groups and, thus, are capable of formingpharmaceutically-acceptable salts with pharmaceutically-acceptablebases. The term “pharmaceutically-acceptable salts” in these instancesrefers to the relatively non-toxic, inorganic and organic base additionsalts of compounds of the present disclosure. These salts can likewisebe prepared in situ in the administration vehicle or the dosage formmanufacturing process or by separately reacting the purified compound inits free acid form with a suitable base, such as the hydroxide,carbonate or bicarbonate of a pharmaceutically-acceptable metal cation,with ammonia or with a pharmaceutically-acceptable organic primary,secondary or tertiary amine. Representative alkali or alkaline earthsalts include the lithium, sodium, potassium, calcium, magnesium andaluminum salts and the like. Representative organic amines useful forthe formation of base addition salts include ethylamine, diethylamine,ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically-acceptable antioxidants include: watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like;oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol and the like; and metal chelating agents, suchas citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid and the like.

Formulations of the present disclosure include those suitable for oral,nasal, topical (including buccal and sublingual), rectal, vaginal and/orparenteral administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient which canbe combined with a carrier material to produce a single dosage form willvary depending upon the host being treated, the particular mode ofadministration. The amount of active ingredient that can be combinedwith a carrier material to produce a single dosage form will generallybe that amount of the compound which produces a therapeutic effect.Generally, this amount will range from about 1% to about 99% of activeingredient, preferably from about 5% to about 70%, most preferably fromabout 10% to about 30%.

In certain embodiments, a formulation of the present disclosurecomprises an excipient selected from the group consisting ofcyclodextrins, liposomes, micelle forming agents, e.g., bile acids andpolymeric carriers, e.g., polyesters and polyanhydrides; and a compoundof the present disclosure. In certain embodiments, an aforementionedformulation renders orally bioavailable a compound of the presentdisclosure.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present disclosure withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present disclosure withliquid carriers or finely divided solid carriers or both and then, ifnecessary, shaping the product.

Formulations of the disclosure suitable for oral administration may bein the form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules or as a solution or a suspension in an aqueous or non-aqueousliquid or as an oil-in-water or water-in-oil liquid emulsion or as anelixir or syrup or as pastilles (using an inert base, such as gelatinand glycerin or sucrose and acacia) and/or as mouth washes and the like,each containing a predetermined amount of a compound of the presentdisclosure as an active ingredient. A compound of the present disclosuremay also be administered as a bolus, electuary or paste.

In solid dosage forms of the disclosure for oral administration(capsules, tablets, pills, dragees, powders, granules and the like), theactive ingredient is mixed with one or more pharmaceutically-acceptablecarriers, such as sodium citrate or dicalcium phosphate and/or any ofthe following: fillers or extenders, such as starches, lactose, sucrose,glucose, mannitol and/or silicic acid; binders, such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,sucrose and/or acacia; humectants, such as glycerol; disintegratingagents, such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; solution retardingagents, such as paraffin; absorption accelerators, such as quaternaryammonium compounds; wetting agents, such as, for example, cetyl alcohol,glycerol monostearate and non-ionic surfactants; absorbents, such askaolin and bentonite clay; lubricants, such a talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfateand mixtures thereof; and coloring agents. In the case of capsules,tablets and pills, the pharmaceutical compositions may also comprisebuffering agents. Solid compositions of a similar type may also beemployed as fillers in soft and hard-shelled gelatin capsules using suchexcipients as lactose or milk sugars, as well as high molecular weightpolyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made in asuitable machine in which a mixture of the powdered compound ismoistened with an inert liquid diluent.

The tablets and other solid dosage forms of the pharmaceuticalcompositions of the present disclosure, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be formulated for rapid release,e.g., freeze-dried. They may be sterilized by, for example, filtrationthrough a bacteria-retaining filter or by incorporating sterilizingagents in the form of sterile solid compositions that can be dissolvedin sterile water or some other sterile injectable medium immediatelybefore use. These compositions may also optionally contain opacifyingagents and may be of a composition that they release the activeingredient(s) only or preferentially, in a certain portion of thegastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions that can be used include polymeric substances andwaxes. The active ingredient can also be in micro-encapsulated form, ifappropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of thedisclosure include pharmaceutically acceptable emulsions,microemulsions, solutions, suspensions, syrups and elixirs. In additionto the active ingredient, the liquid dosage forms may contain inertdiluents commonly used in the art, such as, for example, water or othersolvents, solubilizing agents and emulsifiers, such as ethyl alcohol,isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (inparticular, cottonseed, groundnut, corn, germ, olive, castor and sesameoils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth and mixtures thereof.

Formulations of the pharmaceutical compositions of the disclosure forrectal or vaginal administration may be presented as a suppository,which may be prepared by mixing one or more compounds of the disclosurewith one or more suitable nonirritating excipients or carrierscomprising, for example, cocoa butter, polyethylene glycol, asuppository wax or a salicylate and which is solid at room temperature,but liquid at body temperature and, therefore, will melt in the rectumor vaginal cavity and release the active compound.

Formulations of the present disclosure which are suitable for vaginaladministration also include pessaries, tampons, creams, gels, pastes,foams or spray formulations containing such carriers as are known in theart to be appropriate.

Dosage forms for the topical or transdermal administration of a compoundof this disclosure include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically-acceptablecarrier and with any preservatives, buffers or propellants which may berequired.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this disclosure, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide or mixtures thereof.

Powders and sprays can contain, in addition to a compound of thisdisclosure, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present disclosure to the body. Dissolvingor dispersing the compound in the proper medium can make such dosageforms. Absorption enhancers can also be used to increase the flux of thecompound across the skin. Either providing a rate controlling membraneor dispersing the compound in a polymer matrix or gel can control therate of such flux.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this disclosure.

Pharmaceutical compositions of this disclosure suitable for parenteraladministration comprise one or more compounds of the disclosure incombination with one or more pharmaceutically-acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containsugars, alcohols, antioxidants, buffers, bacteriostats, solutes whichrender the formulation isotonic with the blood of the intended recipientor suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers, which may beemployed in the pharmaceutical compositions of the disclosure includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol and the like) and suitable mixtures thereof,vegetable oils, such as olive oil and injectable organic esters, such asethyl oleate. Proper fluidity can be maintained, for example, by the useof coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms upon the subject compounds may be ensuredby the inclusion of various antibacterial and antifungal agents, forexample, paraben, chlorobutanol, phenyl sorbic acid and the like. It mayalso be desirable to include isotonic agents, such as sugars, sodiumchloride and the like into the compositions. In addition, prolongedabsorption of the injectable pharmaceutical form may be brought about bythe inclusion of agents which delay absorption such as aluminummonostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally-administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer andthe nature of the particular polymer employed, the rate of drug releasecan be controlled. Examples of other biodegradable polymers includepoly(orthoesters) and poly(anhydrides). Depot injectable formulationsare also prepared by entrapping the drug in liposomes or microemulsions,which are compatible with body tissue.

6. Dosing

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.

The phrases “systemic administration,” “administered systemically,”“peripheral administration” and “administered peripherally” as usedherein mean the administration of a compound, drug or other materialother than directly into the central nervous system, such that it entersthe patient's system and, thus, is subject to metabolism and other likeprocesses, for example, subcutaneous administration.

These compounds may be administered to humans and other animals fortherapy by any suitable route of administration, including orally,nasally, as by, for example, a spray, rectally, intravaginally,parenterally, intracistemally and topically, as by powders, ointments ordrops, including buccally and sublingually.

Regardless of the route of administration selected, the compounds of thepresent disclosure, which may be used in a suitable hydrated form and/orthe pharmaceutical compositions of the present disclosure, areformulated into pharmaceutically-acceptable dosage forms by conventionalmethods known to those of skill in the art.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this disclosure may be varied so as to obtain an amountof the active ingredient that is effective to achieve the desiredtherapeutic response for a particular patient, composition and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentdisclosure employed or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion ormetabolism of the particular compound being employed, the duration ofthe treatment, other drugs, compounds and/or materials used incombination with the particular compound employed, the age, sex, weight,condition, general health and prior medical history of the patient beingtreated and like factors well known in the medical arts. A daily, weeklyor monthly dosage (or other time interval) can be used.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the disclosure employed in thepharmaceutical composition at levels lower than that required to achievethe desired therapeutic effect and then gradually increasing the dosageuntil the desired effect is achieved.

In general, a suitable daily dose of a compound of the disclosure willbe that amount of the compound that is the lowest dose effective toproduce a therapeutic effect (e.g., inhibit necrosis). Such an effectivedose will generally depend upon the factors described above. Generallydoses of the compounds of this disclosure for a patient, when used forthe indicated effects, will range from about 0.0001 to about 100 mg perkg of body weight per day. Preferably the daily dosage will range from0.001 to 50 mg of compound per kg of body weight and even morepreferably from 0.01 to 10 mg of compound per kg of body weight.

If desired, the effective daily dose of the active compound may beadministered as two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms.

In certain embodiments, the present disclosure relates to compounds forinhibiting cell death, wherein the compounds are represented bystructures (I). In certain embodiments, the compounds of the presentdisclosure are inhibitors of cell death. In any event, the compounds ofthe present disclosure preferably exert their effect on inhibiting celldeath at a concentration less than about 50 micromolar, more preferablyat a concentration less than about 10 micromolar and most preferably ata concentration less than 1 micromolar.

The compounds of the disclosure can be tested in standard animal modelsof stroke and standard protocols such as described by Hara, H., et al.Proc Natl Acad Sci USA, 1997. 94(5): 2007-12.

When the compounds of the present disclosure are administered aspharmaceuticals, to humans and animals, they can be given per se or as apharmaceutical composition containing, for example, 0.1% to 99.5% (morepreferably, 0.5% to 90%) of active ingredient in combination with apharmaceutically acceptable carrier.

The compounds of the present application or the compositions thereof maybe administered once, twice, three or four times daily, using anysuitable mode described above. Also, administration or treatment withthe compounds may be continued for a number of days; for example,commonly treatment would continue for at least 7 days, 14 days or 28days, for one cycle of treatment. Treatment cycles are well known andare frequently alternated with resting periods of about 1 to 28 days,commonly about 7 days or about 14 days, between cycles. The treatmentcycles, in certain embodiments, may also be continuous.

When administered orally, the total daily dosage for a human subject maybe between 1 mg and 1,000 mg, between about 1,000-2,000 mg/day, betweenabout 10-500 mg/day, between about 50-300 mg/day, between about 75-200mg/day or between about 100-150 mg/day.

The daily dosage may also be described as a total amount of a compounddescribed herein administered per dose or per day. Daily dosage of acompound may be between about 1 mg and 4,000 mg, between about 2,000 to4,000 mg/day, between about 1 to 2,000 mg/day, between about 1 to 1,000mg/day, between about 10 to 500 mg/day, between about 20 to 500 mg/day,between about 50 to 300 mg/day, between about 75 to 200 mg/day orbetween about 15 to 150 mg/day.

In certain embodiments, the method comprises administering to thesubject an initial daily dose of about 1 to 800 mg of a compounddescribed herein and increasing the dose by increments until clinicalefficacy is achieved. Increments of about 5, 10, 25, 50 or 100 mg can beused to increase the dose. The dosage can be increased daily, everyother day, twice per week or once per week.

In certain embodiments, a compound or pharmaceutical preparation isadministered orally. In certain embodiments, the compound orpharmaceutical preparation is administered intravenously. Alternativeroutes of administration include sublingual, intramuscular andtransdermal administrations.

The preparations of the present disclosure may be given orally,parenterally, topically or rectally. They are of course given in formssuitable for each administration route. For example, they areadministered in tablets or capsule form, by injection, inhalation, eyelotion, ointment, suppository, etc. administration by injection,infusion or inhalation; topical by lotion or ointment; and rectal bysuppositories. In certain embodiments, the administration is oral.

7. Combinations

In another aspect of the disclosure the compounds can be administered incombination with other agents, including (but not limited to) compoundsthat are apoptosis inhibitors; PARP poly(ADP-ribose) polymeraseinhibitors; Src inhibitors; agents for the treatment of cardiovasculardisorders; anti-inflammatory agents, anti-thrombotic agents;fibrinolytic agents; anti-platelet agents, lipid reducing agents, directthrombin inhibitors; glycoprotein IIb/IIIa receptor inhibitors; calciumchannel blockers; beta-adrenergic receptor blocking agents;cyclooxygenase (e.g., COX-1 and COX-2) inhibitors; angiotensin systeminhibitor (e.g., angiotensin-converting enzyme (ACE) inhibitors); renininhibitors; and/or agents that bind to cellular adhesion molecules andinhibit the ability of white blood cells to attach to such molecules(e.g., polypeptides, polyclonal and monoclonal antibodies).

Embodiments of the disclosure also provide combinations of two or morecompounds that inhibit cellular necrosis (e.g., a compound as disclosedherein and an additional agent for inhibiting necrosis). The disclosurealso provides combinations of one or more compounds that inhibitcellular necrosis combined with one or more additional agents orcompounds (e.g., other therapeutic compounds for treating a disease,condition or infection such as an apoptosis inhibitor).

8. Kits

Provided herein are also kits that include a compound of the disclosure,combinations, or a pharmaceutically acceptable salt, prodrug,stereoisomer or a mixture of stereoisomers thereof and suitablepackaging. In certain embodiments, a kit further includes instructionsfor use. In one aspect, a kit includes a compound of the disclosure or apharmaceutically acceptable salt, prodrug, stereoisomer or a mixture ofstereoisomers thereof and a label and/or instructions for use of thecompounds in the treatment of the indications, including the diseases orconditions, described herein.

Provided herein are also articles of manufacture that include a compounddescribed herein or a pharmaceutically acceptable salt, prodrug,stereoisomer or a mixture of stereoisomers thereof in a suitablecontainer. The container may be a vial, jar, ampoule, preloaded syringeand intravenous bag.

The kit can also contain instructions for using the compounds accordingto the disclosure. The kit can be compartmentalized to receive thecontainers in close confinement. As used herein, a kit such as acompartmentalized kit includes any kit in which compounds or agents arecontained in separate containers. Illustrative examples of suchcontainers include, but are not limited to, small glass containers,plastic containers or strips of plastic or paper. Particularly preferredtypes of containers allow the skilled worker to efficiently transferreagents from one compartment to another compartment such that thesamples and reagents are not cross-contaminated and the agents orsolutions of each container can be added in a quantitative fashion fromone compartment to another. Such containers include, but are not limitedto, a container that will accept a compound or combination of compoundsand/or other agents of the disclosure. One or more compounds or agentscan be provided as a powder (e.g. lyophilized powder) or precipitate.Such compound(s) can be resuspended prior to administration in asolution that may be provided as part of the kit or separatelyavailable. A kit can contain compounds or agents in other forms such asliquids, gels, solids, as described herein. Different compounds and/oragents may be provided in different forms in a single kit.

EXAMPLES

The examples and preparations provided below further illustrate andexemplify the compounds of the present disclosure and methods fortesting such compounds. It is to be understood that the scope of thepresent disclosure is not limited in any way by the scope of thefollowing examples. In the following examples and throughout thespecification and claims, molecules with a chiral center, unlessotherwise noted, exist as a racemic mixture. Single enantiomers may beobtained by methods known to those skilled in the art and describedherein. Compounds were named by using either ChemBioDraw Ultra 13.0 orChemAxon.

General Procedures

All solvents used were commercially available and were used withoutfurther purification. Reactions were typically run using anhydroussolvents under an inert atmosphere of nitrogen.

Analytical Methods

¹H Nuclear magnetic resonance (NMR) spectroscopy was carried out usingone of the following instruments: a Bruker Avance 400 instrumentequipped with probe DUAL 400 MHz S1, a Bruker Avance 400 instrumentequipped with probe 6 S1 400 MHz 5 mm ¹H-¹³C ID, a Bruker Avance III 400instrument with nanobay equipped with probe Broadband BBFO 5 mm direct,a 400 MHz Agilent Direct Drive instrument with ID AUTO-X PFG probe, alloperating at 400 MHz, or an Agilent VNMRS500 Direct Drive instrumentequipped with a 5 mm Triple Resonance ¹H{¹³C/¹⁵N} cryoprobe operating at500 MHz. The spectra were acquired in the stated solvent at around roomtemperature unless otherwise stated. In all cases, NMR data wereconsistent with the proposed structures. Characteristic chemical shifts(δ) are given in parts-per-million using conventional abbreviations fordesignation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q,quartet; dd, doublet of doublets; dt, doublet of triplets; br, broad.

Where thin layer chromatography (TLC) has been used it refers to silicagel TLC using silica gel F254 (Merck) plates, Rf is the distancetravelled by the compound divided by the distance travelled by thesolvent on a TLC plate. Column chromatography was performed using anautomatic flash chromatography (Biotage SP1 or Isolera) system overBiotage silica gel cartridges (KP-Sil or KP-NH) or in the case ofreverse phase chromatography over Biotage C18 cartridges (KP-C18).

Liquid Chromatography-Mass Spectrometry Method A:

Total ion current (TIC) and DAD UV chromatographic traces together withMS and UV spectra associated with the peaks were taken on a UPLC/MSAcquity™ system equipped with PDA detector and coupled to a Waterssingle quadrupole mass spectrometer operating in alternated positive andnegative electrospray ionization mode. [LC/MS-ES (+/−): analysesperformed using an Acquity UPLC™ CSH, C18 column (50×2.1 mm, 1.7 μmparticle size), column temperature 40° C., mobile phase: A-water+0.1%HCOOH/B—CH₃CN+0.1% HCOOH, flow rate: 1.0 mL/min, runtime=2.0 min,gradient: t=0 min 3% B, t=1.5 min 99.9% B, t=1.9 min 99.9% B, t=2.0 min3% B, stop time 2.0 min. Positive ES 100-1000, Negative ES 100-1000, UVdetection DAD 210-350 nm.

Liquid Chromatography-Mass Spectrometry Method B:

Total ion current (TIC) and DAD UV chromatographic traces together withMS and UV spectra associated with the peaks were taken on a UPLC/MSAcquity™ system equipped with PDA detector and coupled to a Waterssingle quadrupole mass spectrometer operating in alternated positive andnegative electrospray ionization mode. [LC/MS-ES (+/−): analysesperformed using an Acquity UPLC™ BEH, C18 column (50×2.1 mm, 1.7 μmparticle size), column temperature 40° C., mobile phase: A-0.1% v/vaqueous ammonia solution pH 10/B—CH₃CN, flow rate: 1.0 mL/min,runtime=2.0 min, gradient: t=0 min 3% B, t=1.5 min 99.9% B, t=1.9 min99.9% B, t=2.0 min 3% B, stop time 2.0 min. Positive ES 100-1000,Negative ES 100-1000, UV detection DAD 210-350 nm.

Liquid Chromatography-Mass Spectrometry Method C:

Total ion current (TIC) and DAD UV chromatographic traces together withMS and UV spectra associated with the peaks were taken on a UPLC/MSAcquity™ system equipped with PDA detector and coupled to a Waterssingle quadrupole mass spectrometer operating in alternated positive andnegative electrospray ionization mode. The column used was a CortecsUPLC C18, 1.6 μm, 2.1×50 mm. A linear gradient was applied, starting at95% A (A: 0.1% formic acid in water) and ending at 95% B (B: 0.1% formicacid in MeCN) over 2.0 min with a total run time of 2.5 min. The columntemperature was at 40° C. with the flow rate of 0.8 mL/min.

Liquid Chromatography-Mass Spectrometry Method D:

LCMS analyses were performed on a SHIMADZU LCMS consisting of an UFLC20-AD and LCMS 2020 MS detector. The Diode Array Detector was scannedfrom 190-400 nm. The mass spectrometer was equipped with an electrosprayion source (ESI) operated in a positive or negative mode. The massspectrometer was scanned between m/z 90-900 with a scan time from 0.5 to1.0 s. The column used was a Shim-pack XR-ODS, 2.2 μm, 3.0×50 mm. Alinear gradient was applied, starting at 95% A (A: 0.05% TFA in water)and ending at 100% B (B: 0.05% TFA in MeCN) over 2.2 min with a totalrun time of 2.6 min. The column temperature was at 40° C. with a flowrate of 1.0 mL/min.

Liquid Chromatography-Mass Spectrometry Method E:

LCMS analyses were performed on a SHIMADZU LCMS consisting of an UFLC20-AD and LCMS 2020 MS detector. The Diode Array Detector was scannedfrom 190-400 nm. The mass spectrometer was equipped with an electrosprayion source (ESI) operated in a positive or negative mode. The massspectrometer was scanned between m/z 90-900 with a scan time from 0.5 to1.0 s. The column used was a Shim-pack XR-ODS, 2.2 μm, 3.0×50 mm. Alinear gradient was applied, starting at 95% A (A: 0.05% TFA in water)and ending at 100% B (B: 0.05% TFA in MeCN) over 3.2 min with a totalrun time of 3.6 min. The column temperature was at 40° C. with a flowrate of 1.0 mL/min.

Liquid Chromatography-Mass Spectrometry Method F:

LCMS analyses were performed on a SHIMADZU LCMS consisting of an UFLC20-AD and LCMS 2020 MS detector. The Diode Array Detector was scannedfrom 190-400 nm. The mass spectrometer was equipped with an electrosprayion source (ESI) operated in a positive or negative mode. The massspectrometer was scanned between m/z 90-900 with a scan time from 0.5 to1.0 s. The column used was an Ascentis Express C18, 2.7 μm, 3.0×50 mm. Alinear gradient was applied, starting at 95% A (A: 0.05% TFA in water)and ending at 100% B (B: 0.05% TFA in MeCN) over 1.8 min with a totalrun time of 2.0 min. The column temperature was at 45° C. with a flowrate of 1.5 mL/min.

Liquid Chromatography-Mass Spectrometry Method G:

LCMS analyses were performed on a SHIMADZU LCMS consisting of an UFLC20-AD and LCMS 2020 MS detector. The Diode Array Detector was scannedfrom 190-400 nm. The mass spectrometer was equipped with an electrosprayion source (ESI) operated in a positive or negative mode. The massspectrometer was scanned between m/z 90-900 with a scan time from 0.5 to1.0 s. The column used was a Kinetex EVO, 2.6 μm, 3.0×50 mm. A lineargradient was applied, starting at 90% A (A: 0.05% NH₄HCO₃ in water) andending at 95% B (B: MeCN) over 1.7 min with a total run time of 2.0 min.The column temperature was at 40° C. with a flow rate of 1.3 mL/min.

Liquid Chromatography-Mass Spectrometry Method H:

LCMS analyses were performed on a SHIMADZU LCMS consisting of an UFLC20-AD and LCMS 2020 MS detector. The Diode Array Detector was scannedfrom 190-400 nm. The mass spectrometer was equipped with an electrosprayion source (ESI) operated in a positive or negative mode. The massspectrometer was scanned between m/z 90-900 with a scan time from 0.5 to1.0 s. The column used was a Kinetex EVO, 2.6 μm, 3.0×50 mm. A lineargradient was applied, starting at 90% A (A: 0.05% NH₄HCO₃ in water) andending at 95% B (B: MeCN) over 2.7 min with a total run time of 3.0 min.The column temperature was at 40° C. with a flow rate of 1.3 mL/min.

Liquid Chromatography-Mass Spectrometry Method I: The column used was aPoroshell HPH-C18, 2.7 μm, 3.0×50 mm. A linear gradient was applied,starting at 95% A (A: 0.05% NH₄HCO₃ in water) and ending at 95% B (B:0.05% NH₄HCO₃ in MeCN) over 1.8 min with a total run time of 2 min. Thecolumn temperature was at 45° C. with the flow rate of 1.5 mL/min.

Liquid Chromatography-Mass Spectrometry Method J:

LCMS analyses were performed on a SHIMADZU LCMS consisting of an UFLC20-AD and LCMS 2020 MS detector. The Diode Array Detector was scannedfrom 190-400 nm. The mass spectrometer was equipped with an electrosprayion source (ESI) operated in a positive or negative mode. The massspectrometer was scanned between m/z 90-900 with a scan time from 0.5 to1.0 s. The column used was an Ascentis Express C18, 2.7 μm, 2.1×50 mm. Alinear gradient was applied, starting at 90% A (A: 0.10% formic acid inwater) and ending at 95% B (B: 0.10% formic acid in MeCN) over 2.70 minwith a total run time of 3.0 min. The column temperature was at 45° C.with a flow rate of 1.0 mL/min.

Liquid Chromatography-Mass Spectrometry Method K:

The column used was an Agilent Poroshell HPH-C18, 2.7 μm, 3.0×50 mm. Alinear gradient was applied, starting at 95% A (A: 0.05% NH₄HCO₃ inwater) and ending at 95% B (B: 0.05% NH₄HCO₃ in MeCN) over 1.8 min witha total run time of 2.0 min. The column temperature was at 40° C. with aflow rate of 1.5 mL/min.

Liquid Chromatography-Mass Spectrometry Method L:

The column used was a Shim-pack XR-ODS, 2.2 μm, 3.0×50 mm. A lineargradient was applied, starting at 95% A (A: 0.05% TFA in water) andending at 100% B (B: 0.05% TFA in MeCN) over 4.2 min with a total runtime of 5.3 min. The column temperature was at 40° C. with a flow rateof 1.0 mL/min.

Liquid Chromatography-Mass Spectrometry Method M:

The column used was an Ascentis Express C18, 2.7 μm, 3.0×50 mm. A lineargradient was applied, starting at 95% A (A: 0.05% TFA in water) andending at 95% B (B: 0.05% TFA in MeCN) over 4.1 min with a total runtime of 5.3 min. The column temperature was at 40° C. with the flow rateof 1.5 mL/min.

Liquid Chromatography-Mass Spectrometry Method N:

The column used for chromatography was an Xtimate C18 2.1×30 mm, (3 Cpmparticles). Detection methods were diode array (DAD). MS mode waspositive electrospray ionization. MS range was 100-1000. Mobile phase A:0.037% trifluoroacetic acid in water; Mobile phase B: 0.018%trifluoroacetic acid in HPLC grade acetonitrile. The gradient was 5-100%B over 2.00 min. 5% B at 0.00 min, 5-95% B (0.00-1.00 min) 95-100% B(1.00-1.80 min) 100-5% B (1.80-1.81 min) with a hold at 5% B for 0.19min. The flow rate was 1.0 mL/min.

Liquid Chromatography-Mass Spectrometry Method O:

The column used for chromatography was an Xtimate C18 2.1×30 mm, (3 Cpmparticles). Detection methods were diode array (DAD). MS mode waspositive electrospray ionization. MS range was 100-1000. Mobile phase Awas 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018%trifluoroacetic acid in HPLC grade acetonitrile. The gradient was 5-100%B over 2.00 min. 5% B at 0.00 min, 5-95% B (0.00-0.90 min) 95-100% B(0.90-1.80 min) 100-5% B (1.80-1.81 min) with a hold at 5% B for 0.19min. The flow rate was 1.0 mL/min.

Liquid Chromatography-Mass Spectrometry Method P:

The column used for chromatography was an Xbridge Shield RP18 2.1×50 mm,(5 Cpm particles). Detection methods were diode array (DAD). MS mode waspositive electrospray ionization. MS range was 100-1000. Mobile phase Awas 10 mM ammonium bicarbonate in water, and mobile phase B was HPLCgrade acetonitrile. The gradient was 0-60% B over 2.20 min. 0% B at 0.00min, 0-60% B (0.00-0.70 min) with a hold at 60% B for 0.40 min, 60-0% B(1.10-1.11 min) with a hold at 0% B for 1.09 min. The flow rate was 1.0mL/min.

High Performance Liquid Chromatography Method Q:

HPLC (The gradient was holding 0% B for 0.40 min, and then 0-30% B over4.40 min with a hold at 30% B for 0.8 min, 30-0% B over 0.02 min, andthen held at 0% for 0.68 min (0.01-5.21 min: 0.8 mL/min flow rate;5.23-5.90 min: 1.2 ml/min flow rate). Mobile phase A was 0.037%trifluoroacetic acid in water, mobile phase B was 0.018% trifluoroaceticacid in acetonitrile. The column used for chromatography was a 2.0×50 mmLuna-C18(2) column (5 μm particles). Detection methods were diode array(DAD).

Liquid Chromatography-Mass Spectrometry Method R:

The column used for chromatography was an Xbridge Shield RP18 2.1×50 mm,(5 μm particles). Detection methods were diode array (DAD) andevaporative light scattering (ELSD). MS mode was negative electrosprayionization. MS range was 100-1000. Mobile phase A was 10 mM ammoniumbicarbonate in water, and mobile phase B was HPLC grade acetonitrile.The gradient was 0-60% B over 2.20 min. 0% B at 0.00 min, 0-60% B(0.00-0.70 min) with a hold at 60% B for 0.40 min, 60-0% B (1.10-1.11min) with a hold at 0% B for 1.09 min. The flow rate was 1.0 mL/min.

Liquid Chromatography-Mass Spectrometry Method S:

The column used for chromatography was an Xbridge Shield RP18 2.1×50 mm,(5 μm particles). Detection methods were diode array (DAD). MS mode wasnegative electrospray ionization. MS range was 100-1000. Mobile phase Awas 10 mM ammonium bicarbonate in water, and mobile phase B was HPLCgrade acetonitrile. The gradient was 0-60% B over 2.20 min. 0% B at 0.00min, 0-60% B (0.00-0.70 min) with a hold at 60% B for 0.40 min, 60-0% B(1.10-1.11 min) with a hold at 0% B for 1.09 min. The flow rate was 1.0mL/min.

High Performance Liquid Chromatography Method T:

The gradient was 10-80% B over 4.00 min with a hold at 80% B for 0.9min, 80-10% B over 0.02 min, and then held at 10% B for 0.58 min(0.01-4.90 min: 0.8 mL/min flow rate; 4.93-5.50 min: 1.2 mL/min flowrate). Mobile phase A was 10 mM ammonium bicarbonate aqueous solution,mobile phase B was HPLC grade acetonitrile. The column used forchromatography was a 2.1×50 mm Xbridge Shield RPC18 column (5 μmparticles). Detection methods were diode array (DAD).

Compound Preparation

Where the preparation of starting materials is not described, these arecommercially available, known in the literature, or readily obtainableby those skilled in the art using standard procedures. Where it isstated that compounds were prepared analogously to earlier examples orintermediates, it will be appreciated by the skilled person that thereaction time, number of equivalents of reagents and temperature can bemodified for each specific reaction and that it may be necessary ordesirable to employ different work-up or purification techniques. Wherereactions are carried out using microwave irradiation, the microwaveused is a Biotage Initiator. The actual power supplied varies during thecourse of the reaction in order to maintain a constant temperature.

Intermediate 1 3-[(1E)-3-oxoprop-1-en-1-yl]benzonitrile

Four different microwave vials were prepared as follows: Palladium(II)acetate (45 mg, 0.2 mmol) and XPHOS (190 mg, 0.4 mmol) were suspended inanhydrous DMF (5 mL) and the suspension was purged with nitrogen at roomtemperature for 5 min, until a clear solution formed. Then3-bromobenzonitrile (364 mg, 2 mmol) was added, followed by Et₃N (2.23mL, 16 mmol) and 3,3-diethoxyprop-1-ene (0.38 mL, 2.50 mmol). Theresulting mixture was heated under microwave irradiation at 120° C. for20 min. After cooling, 1N HCl solution (5 mL) was added and the mixturewas stirred at room temperature for 30 minutes. The mixtures from allfour vials were pooled together, diluted with EtOAc, and then filteredthrough celite. The organic phase was washed several times with brine,dried over Na₂SO₄, filtered, and evaporated under reduced pressure togive an orange solid. The crude product was purified by columnchromatography (cyclohexane/EtOAc, 90:10 to 70:30) to afford the titlecompound (518 mg, 41%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ9.71 (d, J=7.5 Hz, 1H), 8.29 (s, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.93 (td,J=1.4, 7.8 Hz, 1H), 7.76 (d, J=16.1 Hz, 1H), 7.68 (t, J=7.9 Hz, 1H),7.01 (dd, J=16.1, 7.8 Hz, 1H). LC-MS (Method A): m/z=158.0 [M+H]⁺, 0.78min.

Intermediate 2 methyl 2-(chloromethyl)-2-methylbutanoate

Prepared following the conditions described by Zhang-Jie Shi et al (Org.Lett., 2016, 18 (9), pp 2040-2043). To a stirred solution ofdiisopropylamine (1.68 mL, 12 mmol) in THF (15 mL) was addedn-butyllithium (2.5 M solution in hexanes, 4.8 mL, 12 mmol) dropwise at−78° C. The mixture was stirred at 0° C. for 30 min, then cooled againto −78° C. A solution of methyl 2-methylbutyrate (1.32 mL, 10 mmol) inTHF (5 mL) was added dropwise at −78° C. and the mixture was stirred atthis temperature for 1 h. A solution of chloroiodomethane (0.73 mL, 10mmol) in THF (10 mL) was added dropwise at −78° C. The resulting mixturewas then stirred overnight allowing the temperature to reach roomtemperature. The mixture was quenched with water at 0° C. and extractedwith Et₂O (3×25 mL). The combined organic layers were washed with brine,dried over Na₂SO₄, and evaporated under reduced pressure to afford thetitle compound (1.15 g, crude) as a brown oil. This material was used inthe following step without further purification. ¹H NMR (400 MHz, CDCl₃)δ 3.78-3.73 (m, 4H), 3.57 (d, J=10.8 Hz, 1H), 1.82-1.55 (m, 3H), 1.29(s, 3H), 0.88 (t, J=7.5 Hz, 3H).

Intermediate 3 2-(chloromethyl)-2-methylbutanoic acid

Prepared following the conditions described by Zhang-Jie Shi et al (Org.Lett., 2016, 18 (9), pp 2040-2043). Concentrated HCl (15 mL) wascarefully added at 0° C. to methyl 2-(chloromethyl)-2-methylbutanoate(1.15 g, crude, 7.0 mmol considering as 100% pure). The resultingmixture was stirred at 80° C. The reaction was monitored by ¹H NMR of areaction aliquot quenched with water and extracted with CH₂Cl₂. After 5h a mixture of starting material, presumed desired compound and otherunidentified compounds was observed. The mixture was stirred at 80° C.for an additional 2 h, then left overnight at room temperature. At thispoint an NMR check showed almost complete reversal to the startingmaterial. The mixture was then heated to 100° C. A check after 5 hshowed almost complete conversion to the title compound. Water was addedto the hot mixture and this was extracted twice with CH₂Cl₂. Thecombined organic phases were washed twice with water, dried over Na₂SO₄,filtered and evaporated under reduced pressure to afford a ˜1.75:1mixture of title compound and methyl 2-(chloromethyl)-2-methylbutanoate(630 mg) as a brown oil. This mixture was used in the following stepwithout further purification. ¹H NMR (400 MHz, CDCl₃) only signals fromtitle compound reported δ 3.76 (d, J=11.0 Hz, 1H), 3.60 (d, J=11.0 Hz,1H), 1.86-1.57 (m, 2H), 1.32 (s, 3H), 0.95 (t, J=7.5 Hz, 3H). LC-MS(Method A): m/z=149.0 [M−H]⁻, 0.81 min.

Intermediate 4 4-chloro-2,2-dimethylbutanoyl chloride

3,3-Dimethyloxolan-2-one (1.0 mL, 8.85 mmol) and thionyl chloride (2.58mL, 35.4 mmol) were added to zinc chloride (0.12 g, 0.88 mmol) in amicrowave reaction tube. The tube was capped and the mixture was heatedat 65° C. overnight in a PLS reaction station [CAUTION—pressure build upobserved]. The tube was carefully vented with a needle. The tube wasre-sealed with a fresh cap and heated at 65 DC for a further 6 hours[CAUTION—pressure build up observed]. The tube was carefully vented witha needle. The mixture was evaporated under reduced pressure at roomtemperature to remove the majority of the excess thionyl chloride thenthe dark residue was distilled under reduced pressure in a Kugelrohrapparatus. The major fraction, which distilled at ˜150° C. at 80 mbarwas collected to afford the title compound of ˜90% purity (1.12 g, 75%)as a near colorless liquid. This material was used in the following stepwithout further purification. ¹H NMR (400 MHz, CDCl₃) δ 3.59-3.48 (m,2H), 2.26-2.18 (m, 2H), 1.38 (s, 6H).

Intermediate 54-chloro-2,2-dimethyl-1-(5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)butan-1-one

To a solution of 5-phenyl-4,5-dihydro-1H-pyrazole (423 mg, 2.9 mmol) andDIPEA (1.50 mL, 8.7 mmol) in CH₂Cl₂ (14 mL) at 0° C., was added asolution of 4-chloro-2,2-dimethylbutanoyl chloride (540 mg, 3.19 mmol)in CH₂Cl₂ (1 mL). The mixture was stirred at 0° C. for 30 min, thenconcentrated under reduced pressure. The crude product was purified bycolumn chromatography (cyclohexane/EtOAc, 100:0 to 80:20) to afford thetitle compound (425 mg, 53%) as a pale orange oil. ¹H NMR (400 MHz,CDCl₃)° 7.38-7.30 (m, 2H), 7.29-7.22 (m, 1H), 7.21-7.13 (m, 2H), 6.98(t, J=1.6 Hz, 1H), 5.38 (dd, J=11.9, 4.9 Hz, 1H), 3.50-3.39 (m, 2H),3.34 (ddd, J=18.7, 11.9, 1.8 Hz, 1H), 2.74 (ddd, J=18.7, 4.9, 1.8 Hz,1H), 2.39-2.27 (m, 2H), 1.35 (s, 6H). LC-MS (Method A): m/z=279.1[M+H]⁺, 1.15 min.

Intermediate 6 O1-tert-butyl O3-methyl2-(chloromethyl)-2-ethyl-propanedioate

O3-tert-butyl O1-methyl propanedioate (7.93 g, 39.2 mmol) was slowlyadded to a suspension of sodium hydride (2.04 g, 60%, 51.0 mmol) in DMF(100 mL). The reaction mixture was stirred at rt for 30 min thenchloro(iodo)methane (9.0 g, 51.0 mmol) was added. The reaction mixturewas stirred at rt overnight and then added to 300 mL of ice water. Themixture was extracted with 400 mL of ethyl acetate, washed with water(200 mL×2), brine (150 mL) and concentrated under reduced pressure. Theresidue was purified by flash chromatography to yield the title compoundas a colorless oil (8.7 g, 87%). LCMS (Method C): m/z=251.1, 253.1[M+H]⁺.

Intermediate 7 2-(chloromethyl)-2-methoxycarbonyl-butanoic acid

TFA (50 mL) was added to a solution of O1-tert-butyl O3-methyl2-(chloromethyl)-2-ethyl-propanedioate (8.7 g, 34.7 mmol) in DCM (50mL). The reaction mixture was stirred at rt for 1 h and was thenconcentrated to dryness under reduced pressure. The resulting residuewas taken up in EtOAc (100 mL) and the solution was washed with water(100 mL) and brine (100 mL). The organics were separated and dried overMgSO₄ before concentrating to dryness under reduced pressure to yieldthe title compound as a brown oil (6.4 g, 94.8% yield). LCMS (Method C):m/z=195.1, 197.1 [M+H]⁺.

Intermediate 8 Methyl 2-chlorocarbonyl-2-(chloromethyl)butanoate

2-(chloromethyl)-2-methoxycarbonyl-butanoic acid (6.4 g, 32.9 mmol) wasdissolved in thionyl chloride (50 mL). The reaction mixture was stirredat 75° C. for 2 h and was then concentrated under reduced pressure toyield the title compound as a light brown oil (6.3 g, 90%). ¹H-NMR (400MHz, CDCl₃): δ 4.11-3.98 (m, 2H), 3.86-3.85 (m, 3H), 2.25 (qd, J=7.6,1.0 Hz, 2H), 0.93 (t, J=7.6 Hz, 3H).

Intermediate 9 O1-tert-butyl O3-methyl2-[difluoro(trimethylsilyl)methyl]-2-ethyl-propanedioate

LiHMDS (49.4 mL, 1.0 M, 49.4 mmol) was added to a solution ofO1-tert-butyl O3-methyl 2-ethylpropanedioate (10 g, 49.4 mmol) inanhydrous THF (100 mL) at −78° C. under argon. The mixture was stirredat −78° C. for 30 min before methyl lithium (30.9 mL, 1.6 M, 49.4 mmol)was added. The mixture was stirred at −78° C. for 10 min beforetrimethyl(trifluoromethyl)silane (35.2 g, 247 mmol) was added. Thereaction mixture was warmed slowly to rt and stirred overnight at rt.The reaction was quenched by adding water (100 mL) and extracted withethyl acetate (200 mL×2). The organic layers were combined and washedwith water and brine before concentrating under reduced pressure. Theresulting residue was purified by flash chromatography (20% ethylacetate in hexanes) to yield the desired product as a colorless oil (12g, 75%). LCMS (Method C): m/z=325.3, [M+H]⁺.

Intermediate 10 O1-tert-butyl O3-methyl2-(difluoromethyl)-2-ethyl-propanedioate

Potassium carbonate (12.8 g, 92.5 mmol) was added to a solution ofO1-tert-butyl O3-methyl2-[difluoro(trimethylsilyl)methyl]-2-ethyl-propanedioate (10 g, 30.8mmol) in methanol (100 mL). The reaction mixture was stirred at rt for 1h before concentrating under reduced pressure. The resulting residue wasdissolved in ethyl acetate (250 mL) and washed with water (100 mL×2) andbrine (100 mL) before concentrating under reduced pressure. Theresulting residue was purified by flash chromatography (0-20% ethylacetate in hexanes) to yield the title compound as a colorless oil (7.1g, 28.1 mmol, 91% yield). LCMS (Method C): m/z=253.3 [M+H]⁺.

Intermediate 11 tert-butyl 2-(difluoromethyl)-2-(hydroxymethyl)butanoate

Lithium tri-tert-butoxylaluminohydride (64 mL, 1.7 M, 70.4 mmol) wasadded to a solution of O1-tert-butyl O3-methyl2-(difluoromethyl)-2-ethyl-propanedioate (7.1 g, 28.2 mmol) in THF (100mL) at rt. The reaction mixture was stirred at 75° C. for 5 h underargon. The reaction mixture was cooled to rt and quenched by adding 100mL of sat. aq. NH4Cl solution. The mixture was extracted with ethylacetate (200 mL×2) and the organic layers were combined and washed withwater and brine before concentrating under reduced pressure. Theresulting residue was purified by flash chromatography to provide thetitle compound (3.9 g, 61.2%). LCMS (Method C): m/z=225.3 [M+H]⁺.

Intermediate 12 tert-butyl 2-(chloromethyl)-2-(difluoromethyl)butanoate

Triphenylphosphine (5.47 g, 20.9 mmol) was added to a solution oftert-butyl 2-(difluoromethyl)-2-(hydroxymethyl)butanoate (3.9 g, 17.4mmol) in carbon tetrachloride (60 mL). The reaction mixture was stirredat 76° C. for 12 h. The reaction mixture was concentrated under reducedpressure. Hexanes (50 mL) was added to the resulting residue and thesolid was collected by filtration and washed with 50 mL of hexanes. Thefiltrate was concentrated under reduced pressure and the resultingresidue was purified by flash chromatography (0-25% ethyl acetate inhexanes) to yield the desired product as a colorless oil (3.1 g, 73%).¹H-NMR (400 MHz; CDCl₃): δ 6.12 (t, J=55.2 Hz, 1H), 3.84-3.75 (m, 2H),1.87 (dtd, J=21.8, 14.4, 7.4 Hz, 2H), 1.53-1.48 (m, 9H), 1.03-0.99 (m,3H).

Intermediate 13 2-(chloromethyl)-2-(difluoromethyl)butanoic acid

TFA (30 mL) was added to a solution of tert-butyl2-(chloromethyl)-2-(difluoromethyl)butanoate (5.5 g, 22.7 mmol) in DCM(30 mL). The reaction mixture was stirred at rt for 1 h and thenconcentrated under reduced pressure to provide the desired product.¹H-NMR (400 MHz; CDCl₃): δ 6.19 (t, J=54.8 Hz, 1H), 3.91-3.81 (m, 2H),2.05-1.91 (m, 2H), 1.09-1.05 (m, 3H).

Intermediate 14 2-(chloromethyl)-2-(difluoromethyl)butanoyl chloride

2-(Chloromethyl)-2-(difluoromethyl)butanoic acid (3.9 g, 20.9 mmol) wasdissolved in thionyl chloride (50 mL). The mixture was stirred at 68° C.for 2 h. The reaction mixture was concentrated under reduced pressure toyield the desired product as a light brown oil. ¹H-NMR (400 MHz; CDCl₃):δ 6.25 (t, J=54.4 Hz, 1H), 3.94-3.84 (m, 2H), 2.13-1.97 (m, 2H),1.13-1.09 (m, 3H).

Intermediate 153-(3-fluorophenyl)-6-methyl-2,3,6,7-tetrahydro-1H-pyrazolo[1,2-a]pyrazol-5-one

Sodium cyanoborohydride (0.5 g, 8.3 mmol) was added to a solution of3-bromo-1-[3-(3-fluorophenyl)-3,4-dihydropyrazol-2-yl]-2-methyl-propan-1-one(1.3 g, 4.2 mmol) in acetic acid (50 mL). The reaction mixture wasstirred at 90° C. for 18 h before concentrating to dryness. The crudematerial was purified by flash chromatography eluting with 0-80% EtOAcin hexanes to provide the title compound. ¹H NMR (400 MHz, CDCl₃): δ7.33-7.29 (m, 1H), 7.10 (ddt, J=7.6, 1.6, 0.8 Hz, 1H), 7.05-7.02 (m,1H), 6.98-6.93 (m, 1H), 5.06 (t, J=7.8 Hz, 1H), 3.90 (t, J=8.9 Hz, 1H),3.41-3.37 (m, 1H), 3.20-3.10 (m, 1H), 2.84 (dddd, J=12.6, 8.6, 6.5, 2.2Hz, 1H), 2.57-2.44 (m, 2H), 2.31 (ddt, J=12.6, 10.4, 7.0 Hz, 1H), 1.28(d, J=7.1 Hz, 3H).

Intermediate 165-(cyclopropylmethyl)-2,2,5-trimethyl-1,3-dioxane-4,6-dione

Bromomethylcyclopropane (5.7 g, 42.2 mmol) was added to a mixture of2,2,5-trimethyl-1,3-dioxane-4,6-dione (5.2 g, 32.9 mmol) and potassiumcarbonate (13.6 g, 99 mmol) in DMF (50 mL). The reaction mixture wasstirred at rt overnight then concentrated to dryness. The resultingresidue was taken up in EtOAc (200 mL) and washed with 2×100 mL waterand 1×150 mL saturated brine solution. The organics were separated anddried over MgSO₄ before concentrating to dryness. The crude product waspurified by flash column chromatography eluting with 20% EtOAc inhexanes to provide the title compound. ¹H-NMR (400 MHz; CDCl₃): δ 2.02(d, J=7.2 Hz, 2H), 1.78 (m, 6H), 1.62 (s, 3H), 0.71-0.64 (m, 1H),0.51-0.46 (m, 2H), 0.22-0.18 (m, 2H).

Intermediate 17 2-(cyclopropylmethyl)-3-methoxy-2-methyl-3-oxo-propanoicacid

Sodium methoxide (1.08 g, 30% in methanol, 6.0 mmol) was added to asolution of 5-(cyclopropylmethyl)-2,2,5-trimethyl-1,3-dioxane-4,6-dionein methanol (30 mL). The reaction mixture was stirred at rt for 1 h thenconcentrated to dryness. The resulting residue was taken up in EtOAc(100 mL) and washed with 2×100 mL water and 1×150 mL saturated brinesolution. The organics were separated and dried over MgSO₄ beforeconcentrating to dryness. The crude product was purified by flash columnchromatography eluting with 50% EtOAc in hexanes to provide the titlecompound as a colorless oil (340 mg, 91%). LCMS (Method C): m/z=187.1[M+H]⁺.

Intermediate 18 2-(cyclopropylmethyl)-3-hydroxy-2-methyl-propanoic acid

To a solution of2-(cyclopropylmethyl)-3-methoxy-2-methyl-3-oxo-propanoic acid (343 mg,1.84 mmol) in THF (10 mL) and Methanol (1 mL) was added LithiumBorohydride (160 mg, 7.4 mmol) in 5 portions. The reaction mixture wasstirred at rt for 1 h before quenching by adding water (100 mL). Themixture was extracted with EtOAc (100 mL×3). The organics were combinedand washed with saturated brine solution (100 mL) and dried (MgSO₄)before concentration to dryness. The crude product was purified by flashcolumn chromatography eluting with 50% EtOAc in hexanes to provide thetitle compound as a colorless oil (145 mg, 50%). LCMS (Method C):m/z=159.1 [M+H]⁺.

Intermediate 19 2-(chloromethyl)-3-cyclopropyl-2-methyl-propanoylchloride

A solution of 2-(cyclopropylmethyl)-3-hydroxy-2-methyl-propanoic acid(159 mg, 1 mmol) in thionyl chloride (3 mL) was heated at 80° C. for 2h. The reaction mixture was concentrated in vacuo and used directly inthe next step without purification. LCMS (Method C): m/z=177.1, 179.1[M+H]⁺ (corresponds to the carboxylate formed upon hydrolysis).

Intermediate 206-(cyclopropylmethyl)-3-(3-fluorophenyl)-2,3,6,7-tetrahydro-1H-pyrazolo[1,2-a]pyrazol-5-one

To a solution of3-(3-fluorophenyl)-2,3,6,7-tetrahydro-1H-pyrazolo[1,2-a]pyrazol-5-one(100 mg, 0.43 mmol) in THF (4.0 mL) and DMPU (55 μL) at −78° C. wasadded KHMDS (0.5M/PhMe, 0.94 mL, 0.47 mmol) and the resulting yellowsolution was stirred at −78° C. for 30 min. Bromomethylcyclopropane (86mg, 0.64 mmol) was added, and the reaction mixture was allowed to warmto rt and was stirred overnight. The reaction mixture was diluted withNH₄Cl solution (15 mL) and EtOAc (15 mL). The layers were separated andthe aqueous layer was extracted with EtOAc (3×15 mL). The combinedorganic layers were dried over MgSO₄, filtered, and concentrated underreduced pressure. The crude reaction mixture was purified employingsilica gel chromatography (0-80% EtOAc/hexanes) to provide the titlecompound as a mixture of diastereomers.

Intermediates 21 and 22 1-tert-butyl 3-methyl2-(difluoro(trimethylsilyl)methyl)-2-methylmalonate and 1-tert-butyl3-methyl 2-(difluoromethyl)-2-methylmalonate

To a solution of 1-tert-butyl 3-methyl 2-methylmalonate (20 g, 106.26mmol) in THF (200 mL) was added LiHMDS (1 M in THF, 106.26 mL) at −78°C. under N₂. The mixture was stirred at −78° C. for 30 min, then MeLi (1M in THF, 106.26 mL) was added. The mixture was stirred for 10 min thenTMSCF₃ (75.55 g, 531.29 mmol) was added. The reaction mixture wasstirred for 16 h while slowly warming to 20° C. The mixture was quenchedslowly with sat. aqueous NH₄Cl (200 mL). The organic phase was separatedand the aqueous phase was extracted with MTBE (2×100 mL). The combinedorganic phase was washed with brine (100 mL), dried with anhydrousNa₂SO₄, filtered and concentrated under reduced pressure to provide thetitle compounds (40 g, crude) as a colorless liquid.

Intermediates 23 and 24 1-tert-butyl 3-methyl2-(1,1-difluoroethyl)-2-methylmalonate and 1-tert-butyl 3-methyl2-(difluoromethyl)-2-methylmalonate

KF (8.98 g, 154.63 mmol) was vacuum dried and added to a mixture of1-tert-butyl 3-methyl2-(difluoro(trimethylsilyl)methyl)-2-methylmalonate, 1-tert-butyl3-methyl 2-(difluoromethyl)-2-methylmalonate (16 g, 51.54 mmol) and CH₃I(21.95 g, 154.63 mmol, 9.63 mL) in DMF (150 mL) at 20° C. under N₂. Themixture was heated at 80° C. and stirred for 6 h. The mixture wasfiltered and the filter cake was washed with MTBE (50 mL). The filtratewas poured into water (500 mL) and extracted with MTBE (3×150 mL). Thecombined organic phase was washed with brine (100 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (PE:MTBE=1:0 to6:1) to give a mixture of the title compounds (11.2 g, 86%) as acolorless liquid.

Intermediates 25 and 26 tert-butyl3,3-difluoro-2-(hydroxymethyl)-2-methylbutanoate and tert-butyl3,3-difluoro-2-(hydroxymethyl)-2-methylpropanoate

To a mixture of 1-tert-butyl 3-methyl2-(1,1-difluoroethyl)-2-methylmalonate and 1-tert-butyl 3-methyl2-(difluoromethyl)-2-methylmalonate (11.2 g, 44.4 mmol) in THF (110 mL)was added LiAlH(Ot-Bu)₃ (1 M in THF, 111 mL) at 20° C. under N₂. Themixture was then heated to 80° C. and stirred for 16 h. The mixture wascooled to 20° C. and quenched with sat. NH₄Cl (300 mL). The mixture wasfiltered and the filter cake was washed with EtOAc (3×70 mL). Thecombined organic phase was washed with brine (100 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (PE:EtOAc=1:0to 6:1) to give a mixture of the title compounds (8.2 g, 82%) as acolorless oil.

Intermediates 27 and 28 tert-butyl2-(chloromethyl)-3,3-difluoro-2-methyl-butanoate and tert-butyl2-(chloromethyl)-3,3-difluoro-2-methyl-propanoate

To a mixture of tert-butyl3,3-difluoro-2-(hydroxymethyl)-2-methylbutanoate and tert-butyl3,3-difluoro-2-(hydroxymethyl)-2-methylpropanoate (7 g, 31.22 mmol) inCCl₄ (70 mL) was added PPh₃ (16.37 g, 62.43 mmol) at 20° C. under N₂.The mixture was then heated to 80° C. and stirred for 6 h. The mixturewas cooled to 25° C., added to hexane (100 mL) and stirred for 5 min.The mixture was filtered and concentrated under reduced pressure to givea mixture of the title compounds (7.2 g crude) as a colorless oil. Theresidue was used in the next step directly.

Intermediates 29 and 30 2-(chloromethyl)-3,3-difluoro-2-methyl-butanoicacid and 2-(chloromethyl)-3,3-difluoro-2-methyl-propanoic Acid

To a mixture of tert-butyl2-(chloromethyl)-3,3-difluoro-2-methyl-butanoate and tert-butyl2-(chloromethyl)-3,3-difluoro-2-methyl-propanoate (7.2 g, 29.67 mmol) inDCM (70 mL) was added TFA (30 mL) at 25° C. under N₂. The mixture wasstirred at 25° C. for 2 h. The mixture was concentrated under reducedpressure. The resulting residue was added to water (60 mL) and adjustedto pH 9-10. The aqueous phase was extracted with EtOAc (20 mL). Theorganic phase was separated and the aqueous phase was adjusted to pH 2-3by the addition of HCl (2 N) and extracted with EtOAc (3×20 mL). Thecombined organic phase was washed with brine (10 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure togive a mixture of the title compounds (4 g, 72%) as a colorless oil,which was used in the next step directly.

Intermediates 31 and 32 2-(chloromethyl)-3,3-difluoro-2-methyl-butanoylchloride and 2-(chloromethyl)-3,3-difluoro-2-methyl-propanoyl Chloride

A mixture of 2-(chloromethyl)-3,3-difluoro-2-methyl-butanoic acid and2-(chloromethyl)-3,3-difluoro-2-methyl-propanoic acid (1 g, 5.36 mmol)in thionyl chloride (10 mL) was heated to 70° C. and stirred for 2 h.The mixture was cooled to 25° C. and concentrated under reduced pressureto give a mixture of the title compounds (0.9 g, 81%) as a light yellowoil, which was used in the next step directly.

Intermediate 33 1-tert-butyl 3-methyl2-(2,2,2-trifluoroethyl)propanedioate

To a solution of 3-tert-butyl 1-methyl propanedioate (50 g, 287.04 mmol,48.54 mL) in DMF (250 mL) was added NaH (14.92 g, 373.15 mmol, 60% inmineral oil) at 0° C. under N₂. The mixture was stirred at 0° C. for 30min before 1,1,1-trifluoro-2-iodo-ethane (78.34 g, 373.15 mmol, 36.61mL) was added at 0° C. The reaction mixture was heated at 50° C. for 12h. The mixture was poured into ice-water (750 mL) and extracted withEtOAc (3×200 mL). The combined organic phase was washed with brine (150mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(PE:EtOAc=10:1 to 1:1) to give the title compound (19.2 g, 26%) as ayellow oil.

Intermediate 341-tert-butyl3-methyl2-[difluoro(trimethylsilyl)methyl]-2-(2,2,2-trifluoroethyl)propanedioate

To a solution of 1-tert-butyl 3-methyl2-(2,2,2-trifluoroethyl)propanedioate (10 g, 39.03 mmol) in THF (100 mL)was added LiHMDS (39.03 mL, 1M in THF) at −78° C. under N₂. The reactionmixture was stirred at −78° C. for 30 min, and then MeLi (39.03 mL, 1M)was added dropwise at −78° C. under N₂. The mixture was stirred at −78°C. for 30 min and TMSCF₃ (27.75 g, 195.15 mmol) was added at −78° C.under N₂, then the reaction solution was stirred at 25° C. for 12 h. Themixture was poured into water (100 mL), extracted with EtOAc (3×50 mL).The combined organic phase was washed with brine (50 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure togive the title compound (9.5 g, 64%) as a yellow oil.

Intermediate 35 1-tert-butyl 3-methyl2-(difluoromethyl)-2-(2,2,2-trifluoroethyl)propanedioate

To a mixture of 1-tert-butyl 3-methyl2-[difluoro(trimethylsilyl)methyl]-2-(2,2,2-trifluoroethyl)propanedioate(9.5 g, 25.11 mmol) in DMF (100 mL) was added KF (4.38 g, 75.32 mmol,1.76 mL) at 25° C. The mixture was heated to 80° C. and stirred for 2 h.The mixture was poured into water (300 mL) and extracted with EtOAc(3×100 mL). The combined organic phase was washed with brine (50 mL),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(PE:EtOAc=20:1 to 5:1) to provide the title compound (5.3 g, 69%) as ayellow oil.

Intermediate 36 tert-butyl2-(difluoromethyl)-4,4,4-trifluoro-2-(hydroxymethyl)butanoate

To a solution of 1-tert-butyl 3-methyl2-(difluoromethyl)-2-(2,2,2-trifluoroethyl)propanedioate (4.1 g, 13.39mmol) in THF (40 mL) was added LiAlH(Ot-Bu)₃ (33.47 mL, 1M) at 25° C.The reaction mixture was stirred at 80° C. for 5 h. The residue waspoured into sat. aq. NH₄Cl (50 mL) at 0° C., stirred for 5 min andextracted with EtOAc (3×50 mL). The combined organic phase was washedwith brine (50 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (PE:EtOAc=100:1 to 4:1) to provide the titlecompound (1.44 g, 39%) as a yellow oil.

Intermediate 37 tert-butyl2-(chloromethyl)-2-(difluoromethyl)-4,4,4-trifluoro-butanoate

To a solution of tert-butyl2-(difluoromethyl)-4,4,4-trifluoro-2-(hydroxymethyl)butanoate (1.4 g,5.03 mmol) in CCl₄ (15 mL) was added PPh₃ (1.58 g, 6.04 mmol) and thesolution was stirred at 80° C. for 12 h. The reaction mixture wasconcentrated under reduced pressure. The resulting residue was dilutedwith MTBE (10 mL), filtered and concentrated under reduced pressure togive the title compound (1.1 g, 74%) as a yellow oil.

Intermediate 382-(chloromethyl)-2-(difluoromethyl)-4,4,4-trifluoro-butanoic acid

To a solution of tert-butyl2-(chloromethyl)-2-(difluoromethyl)-4,4,4-trifluoro-butanoate (1.1 g,3.71 mmol) in DCM (12 mL) was added TFA (11 mL) at 0° C. and the mixturewas stirred at 25° C. for 1 h. The reaction mixture was concentratedunder reduced pressure to remove TFA. The residue was adjusted to pH=7-8by the addition of sat. aq. NaHCO₃ and extracted with EtOAc (3×10 mL).The combined organic phase was washed with brine (10 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure toprovide the title compound (0.85 g, 95%) as a yellow oil.

Intermediate 392-(chloromethyl)-2-(difluoromethyl)-4,4,4-trifluoro-butanoyl chloride

A solution of2-(chloromethyl)-2-(difluoromethyl)-4,4,4-trifluoro-butanoic acid (0.65g, 2.70 mmol) in SOCl₂ (13 mL) was stirred at 68° C. for 1 h. Thereaction mixture was concentrated under reduced pressure to give thetitle compound (520 mg, 74%) as a yellow oil.

Intermediate 40 1-tert-butyl 3-methyl 2-(cyclopropylmethyl)malonate

To a solution of NaH (6.89 g, 172.22 mmol, 60% in mineral oil) in DMF(150 mL) was added tert-butyl methyl malonate (30 g, 172.22 mmol, 29.13mL) and the reaction mixture was stirred at 25° C. for 2 h.Bromomethylcyclopropane (27.9 g, 206.67 mmol, 19.79 mL) was addeddropwise slowly and stirred for 16 h. The reaction mixture was quenchedby the addition of aq. NH₄Cl (300 mL) at 0° C., extracted with EtOAc(3×300 mL), washed with brine (3×300 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (PE:MTBE=100:1 to 4:1) toprovide the title compound (29.5 g, 75%) as a white oil.

Intermediate 41 1-tert-butyl 3-methyl2-(cyclopropylmethyl)-2-[difluoro(trimethylsilyl) methyl] propaedioate

To a solution of 1-tert-butyl 3-methyl2-(cyclopropylmethyl)propanedioate (20 g, 87.61 mmol) in THF (200 mL)was added LiHMDS (87.61 mL, 1 M) at −78° C. The reaction mixture wasstirred at −78° C. for 1 h. MeLi (87.61 mL, 1 M) was added at −78° C.and stirred for 10 min and then TMSCF₃ (62.29 g, 438.05 mmol, 64.75 mL)was added. The reaction mixture was warmed slowly to 25° C. and stirredfor 18 h. The reaction mixture was quenched by the addition of sat. aq.NH₄Cl (200 mL) at 0° C., and then extracted with EtOAc (3×200 mL). Thecombined organic layers were washed with brine (200 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography (PE:MTBE=100:1to 4:1) to give the title compound (27.3 g, 89%) as a light yellowliquid.

Intermediate 42 1-tert-butyl 3-methyl2-(cyclopropylmethyl)-2-(difluoromethyl) propanedioate

To a solution of 1-tert-butyl 3-methyl2-(cyclopropylmethyl)-2-[difluoro(trimethylsilyl) methyl]propanedioate(27 g, 77.04 mmol) in DMF (270 mL) was added KF (13.43 g, 231.12 mmol,5.41 mL) at 25° C. The reaction mixture was heated at 80° C. and stirredfor 2 h under N₂ atmosphere. The reaction mixture was cooled to 25° C.then quenched by the addition of water (300 mL) and extracted with EtOAc(3×300 mL). The combined organic phase was washed with water (150 mL)and brine (300 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to provide the title compound (21 g,98%) as a yellow oil.

Intermediate 432-tert-butoxycarbonyl-2-(cyclopropylmethyl)-3,3-difluoro-propanoic acid

To a solution of 1-tert-butyl 3-methyl2-(cyclopropylmethyl)-2-(difluoromethyl) propanedioate (21 g, 75.46mmol) in THF (200 mL) was added LiAlH(Ot—Bu)₃ (188.65 mL, 1 M) at 25° C.The reaction mixture was stirred at 84° C. for 5 h before quenching bythe addition of sat. aq. NH₄Cl (200 mL). The mixture was extracted withEtOAc (3×200 mL), washed with brine (200 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography (PE:EtOAc=100:1to 4:1) to provide the title compound (8.8 g, 44%) as a yellow oil.

Intermediate 44 tert-butyl2-(chloromethyl)-2-(cyclopropylmethyl)-3,3-difluoro-propanoate

To a solution of tert-butyl2-(cyclopropylmethyl)-3,3-difluoro-2-(hydroxymethyl)propanoate (8.8 g,35.16 mmol) in CCl₄ (100 mL) was added PPh₃ (11.07 g, 42.19 mmol) andthe solution was stirred at 80° C. for 12 h. Hexane (100 mL) was addedand the mixture was filtered and the cake was washed with 100 mL ofhexane. The filtrate was concentrated to give the title compound (8.7 g,92%) as a yellow oil.

Intermediate 452-(chloromethyl)-2-(cyclopropylmethyl)-3,3-difluoro-propanoic acid

To a solution of tert-butyl2-(chloromethyl)-2-(cyclopropylmethyl)-3,3-difluoro-propanoate (3 g,11.16 mmol) in DCM (30 mL) was added TFA (30 mL, 405.19 mmol). Thereaction mixture was stirred at 25° C. for 1 h. The solution wasconcentrated under reduced pressure to provide the title compound (2.3g, 97%) as a yellow oil.

Intermediate 462-(chloromethyl)-2-(cyclopropylmethyl)-3,3-difluoro-propanoyl chloride

A solution of2-(chloromethyl)-2-(cyclopropylmethyl)-3,3-difluoro-propanoic acid (1.2g, 5.64 mmol) in SOCl₂ (20 mL) was stirred at 70° C. for 2 h. Thesolution was concentrated under reduced pressure to provide the titlecompound (1.2 g, 92%) as a yellow oil, which was used in the next stepdirectly.

Intermediate 47 1-tert-butyl 3-methyl 2-allylmalonate

To a mixture of NaH (12.63 g, 315.74 mmol, 60% in mineral oil) in THF(500 mL) was added a solution of tert-butyl methyl malonate (50 g,287.04 mmol) in THF (500 mL) dropwise at 0° C. under N₂. The mixture waswarmed to 25° C. and stirred for 1 h. Then a solution of3-bromoprop-1-ene (38.2 g, 315.74 mmol) in THF (500 mL) was added in oneportion at 25° C. under N₂. The reaction mixture was stirred for 16 h at25° C. The mixture was quenched by the addition of sat. NH₄Cl solution(200 mL), diluted with water (200 mL) and extracted with EtOAc (3×200mL). The combined organics were washed with brine (500 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under vacuum. The residuewas purified by silica gel column chromatography (PE:EtOAc=100 to 20:1)to yield the title compound (20 g, 32%) as a colorless oil.

Intermediate 48 1-tert-butyl 3-methyl2-allyl-2-(difluoro(trimethylsilyl)methyl)malonate

To a solution of 1-tert-butyl 3-methyl 2-allylmalonate (19 g, 88.68mmol) in THF (200 mL) was added LiHMDS (1 M, 88.68 mL, 88.68 mmol)dropwise at −78° C. under N₂. The reaction mixture was stirred for 0.5 hand then MeLi (1 M, 88.68 mL, 88.68 mmol) was added dropwise at −78° C.under N₂. The reaction mixture was stirred for 15 min before TMSCF₃(63.05 g, 443.39 mmol) was added dropwise at −78° C. The mixture waswarmed to 25° C. and stirred for 16 h under N₂. The mixture was quenchedby the addition of sat. NH₄Cl solution (100 mL) and extracted with EtOAc(2×50 mL). The combined organics were washed with brine (100 mL), driedover anhydrous Na₂SO₄, filtered and concentrated under vacuum to providethe title compound (39 g, 78%) as a brown oil.

Intermediate 49 1-tert-butyl 3-methyl 2-allyl-2-(difluoromethyl)malonate

To a solution of 1-tert-butyl 3-methyl2-allyl-2-(difluoro(trimethylsilyl)methyl)malonate (39 g, 69.55 mmol) inTHF (400 mL) was added TBAF (1 M/THF, 139.10 mL, 139.10 mmol) in oneportion at 25° C. The reaction mixture was stirred for 1 h at 70° C.under N₂. The mixture was concentrated under vacuum and the resultingresidue was purified by silica gel column chromatography (PE:EtOAc=50:1)to give the title compound (15.7 g, 85%) as a colorless oil.

Intermediate 50 tert-butyl2-(difluoromethyl)-2-(hydroxymethyl)pent-4-enoate

To a solution of 1-tert-butyl 3-methyl2-allyl-2-(difluoromethyl)malonate (15.7 g, 59.41 mmol) in THF (200 mL)was added LiAlH(Ot—Bu)₃ (1 M, 297.05 mL, 297.05 mmol) in one portion at25° C. The reaction mixture was heated to 80° C. and stirred for 16 h.The reaction was quenched by the addition of sat. NH₄Cl (100 mL) andfiltered through a pad of celite. The filtrate was extracted with EtOAc(2×100 mL). The combined organics were washed with brine (200 mL), driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressureto provide the title compound (14.3 g, 97%) as a light yellow oil.

Intermediate 51 tert-butyl2-(chloromethyl)-2-(difluoromethyl)pent-4-enoate

To a solution of tert-butyl2-(difluoromethyl)-2-(hydroxymethyl)pent-4-enoate (14.3 g, 60.53 mmol)in CCl₄ (200 mL) was added triphenylphosphine (39.69 g, 151.32 mmol) inone portion at 25° C. The reaction mixture was heated at 80° C. for 2 h.The mixture was concentrated under vacuum and the resulting residue waspurified by silica gel column chromatography (PE:EtOAc=50:1) to yieldthe title compound (12.1 g, 78%) as a yellow oil.

Intermediate 52 2-(chloromethyl)-2-(difluoromethyl)pent-4-enoic acid

To a solution of tert-butyl2-(chloromethyl)-2-(difluoromethyl)pent-4-enoate (12.1 g, 47.51 mmol) inanhydrous DCM (200 mL) was added TFA (162.51 g, 1.43 mol) in one portionat 25° C. The reaction mixture was stirred for 16 h at rt. The reactionmixture was diluted with water (50 mL) and concentrated under vacuum toremove TFA. The pH was adjusted to 8 by the addition of saturatedaqueous Na₂CO₃ and washed with EtOAc (3×50 mL). The aqueous layer wasadjusted to pH=3 by the addition of HCl (2 N) and extracted with EtOAc(3×50 mL). The combined organics were washed with brine (100 mL), driedover anhydrous Na₂SO₄, filtered and concentrated under vacuum to providethe title compound (9.4 g, 99%) as a light pink oil.

Intermediate 53 2-(chloromethyl)-2-(difluoromethyl)pent-4-enoyl chloride

A solution of 2-(chloromethyl)-2-(difluoromethyl)pent-4-enoic acid (1 g,5.04 mmol) in SOCl₂ (10 mL) was stirred at 70° C. for 2 h. The reactionmixture was concentrated under vacuum to give the title compound (1.06g, 97%) as a light yellow oil.

Preparation 1 (E)-3-(5-fluoro-3-pyridyl)prop-2-enal

A solution of 5-fluoropyridine-3-carbaldehyde (10 g, 79.94 mmol) and(triphenylphosphoranylidene)acetaldehyde (24.33 g, 79.94 mmol) in DCM(200 mL) was stirred at rt overnight. The reaction mixture was treatedwith silica, evaporated under reduced pressure and purified by columnchromatography eluting with a gradient of ethyl acetate (0 to 100%) inhexanes to provide a light yellow solid. ¹H-NMR (400 MHz, CDCl₃): δ 9.78(d, J=7.4 Hz, 1H), 8.64 (t, J=1.6 Hz, 1H), 8.56 (d, J=2.7 Hz, 1H), 7.62(dddd, J=8.9, 2.7, 1.8, 0.5 Hz, 1H), 7.54-7.49 (m, 1H), 6.79 (dd,J=16.1, 7.4 Hz, 1H).

The following intermediates were prepared using methods analogous to theone described above.

Preparation 2 5-Phenyl-4,5-dihydro-1H-pyrazole

Hydrazine hydrate (65%, 2 mL) was added to a solution of(2E)-3-phenylprop-2-enal (1.0 g, 7.6 mmol) in t-BuOH (12 mL). Theresulting mixture was stirred at 80° C. for 18 h then the reactionmixture was concentrated under reduced pressure. The crude product waspurified by reverse phase column chromatography (water/MeCN, 100:0 to50:50) to afford the title compound (396 mg, 36%) as a colorless oil. ¹HNMR (400 MHz, CDCl₃) δ 7.43-7.23 (m, 5H), 6.87-6.82 (m, 1H), 4.75 (dd,J=10.7, 8.7 Hz, 1H), 3.16 (ddd, J=17.1, 10.8, 1.5 Hz, 1H), 2.74 (ddd,J=17.2, 8.7, 1.8 Hz, 1H). LC-MS (Method A): m/z=147.1 [M+H]⁺, 0.57 min.

The following intermediates were prepared using methods analogous to theone described above.

Preparation 3 5-(3-fluorophenyl)-4,5-dihydro-1H-pyrazole

To a vigorously stirring mixture of (2E)-3-(3-fluorophenyl)prop-2-enal(20 g, 0.133 mol) in ether (500 mL) was added hydrazine hydrate (80%, 66g, 1.33 mol) dropwise. The resulting mixture was stirred at roomtemperature for 0.5 hour and concentrated under vacuum. The residue wasdiluted with water (500 mL) and extracted with ethyl acetate (3×500 mL).The combined organic layers were washed with brine, dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated under vacuumto afford the title compound (15 g crude) as a yellow oil. ¹H NMR (400MHz, DMSO-d₆) δ 7.37 (td, J=7.9, 6.3 Hz, 1H) 7.26 (d, J=3.5 Hz, 1H)7.20-7.10 (m, 2H) 7.03-7.10 (m, 1H) 6.72 (s, 1H) 4.62 (td, J=10.7, 3.8Hz, 1H) 3.06 (ddd, J=16.9, 10.7, 1.8 Hz, 1H) 2.50-2.41 (m, 1H). LC-MS(Method A): m/z=165.0 [M+H]⁺, 0.68 min.

The following intermediates were prepared using methods analogous to theone described above.

Preparation 4 di-tert-butyl3-(5-fluoro-3-pyridyl)-5-hydroxy-pyrazolidine-1,2-dicarboxylate

To a solution of (E)-3-(5-fluoro-3-pyridyl)prop-2-enal (5.9 g, 39.04mmol) in toluene (50 mL) was added(S)-(−)-α,α-Diphenyl-2-pyrrolidinemethanol trimethylsilyl ether (2.92 g,8.98 mmol) followed by tert-butyl N-(tert-butoxycarbonylamino)carbamate(13.6 g, 58.56 mmol). Toluene (23 mL) was used to wash the reactants offthe reaction flask wall and added to the reaction mixture. The reactionvessel was sealed and stirred at rt overnight. The reaction mixture wasloaded directly onto silica gel and purified by flash chromatography(0-100% ethyl acetate in hexanes) to yield the desired product as ayellow solid (9.6 g). LCMS (Method B): m/z=384.3 [M+H]⁺.

The following intermediates were prepared using methods analogous to theone described above.

Preparation 5 3-(4,5-dihydro-1H-pyrazol-5-yl)-5-fluoro-pyridine

To a solution of di-tert-butyl3-(5-fluoro-3-pyridyl)-5-hydroxy-pyrazolidine-1,2-dicarboxylate (2.0 g,5.22 mmol) in DCM (20 mL) was added 2,2,2-trifluoroacetic acid (20 mL).The reaction mixture was stirred at rt for 1 h and was then concentratedunder reduced pressure. The resulting residue was dissolved in ethylacetate (50 mL) and washed with 5% NaHCO₃ (20 mL), water (20 mL) andbrine (20 mL). The organic layer was collected and dried over MgSO₄before concentrating under reduced pressure to yield the crude product(0.75 g, 4.5 mmol), which was used in the next step withoutpurification. LCMS (Method B): m/z=166.1 [M+H]⁺.

The following intermediates were prepared using methods analogous to theone described above.

Preparation 6 Preparation of3-[1-(3-chloro-2,2-dimethylpropanoyl)-4,5-dihydro-1H-pyrazol-5-yl]-5-fluorobenzonitrile

DIPEA (0.39 mL, 2.25 mmol) and 3-chloro-2,2-dimethylpropanoyl chloride(0.16 mL, 1.17 mmol) were added at 0° C. to a solution of3-(4,5-dihydro-1H-pyrazol-5-yl)-5-fluorobenzonitrile (170 mg, 0.90 mmol)in anhydrous CH₂Cl₂ (6 mL). The mixture was stirred at room temperaturefor 1 h then washed with sat. NH₄Cl solution, sat. NaHCO₃ solution andwater. The organic phase was dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography (cyclohexane/EtOAc, 93:7 to 40:60) to give thetitle compound (187 mg, 67%) as a pale yellow oil. ¹H NMR (400 MHz,CDCl₃) δ 7.33 (t, J=1.4 Hz, 1H), 7.26 (ddd, J=7.8, 2.4, 1.3 Hz, 1H),7.20 (td, J=2.0, 9.0 Hz, 1H), 7.01 (t, J=1.6 Hz, 1H), 5.42 (dd, J=12.0,5.3 Hz, 1H), 4.14 (d, J=10.5 Hz, 1H), 3.83 (d, J=10.5 Hz, 1H), 3.43(ddd, J=18.9, 12.1, 1.6 Hz, 1H), 2.71 (ddd, J=18.8, 5.5, 1.8 Hz, 1H),1.41 (s, 3H), 1.40 (s, 3H). LC-MS (Method A): m/z=308.2 [M+H]⁺, 1.07min.

The following intermediates were prepared using methods analogous to theone described above.

Preparation 72-(chloromethyl)-1-[5-(3-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl]-2-methylbutan-1-one

2-(Chloromethyl)-2-methylbutanoic acid (366 mg, ˜64 mol %, ˜1.5 mmol)was dissolved in CH₂Cl₂ (3 mL) and oxalyl chloride (0.127 mL, 1.5 mmol)was added at 0° C. followed by one drop of DMF. The mixture was stirredat room temperature for 3.5 h. This mixture was then added dropwise at0° C. to a stirred solution of5-(3-fluorophenyl)-4,5-dihydro-1H-pyrazole (164 mg, 1.0 mmol) and DIPEA(0.521 mL, 3 mmol) in CH₂Cl₂ (4 mL). The mixture was stirred at roomtemperature for 3 h then diluted with CH₂Cl₂ and washed with sat. NaHCO₃solution, with sat. NH₄Cl solution and with brine. The organic phase wasdried over Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude product was purified by column chromatography (cyclohexane/EtOAc,100:0 to 60:40) to afford a yellow oil (72 mg) which contains the titlecompound as a mixture of diastereoisomers plus unidentifiedside-products. This mixture was used in the following step withoutfurther purification. LC-MS (Method A): m/z=297.2 [M+H]⁺, 1.18 min.

The following intermediates were prepared using methods analogous to theone described above.

Example 1 Procedure A(7S)-2,2-dimethyl-7-phenyl-hexahydropyrazolo[1,2-a]pyrazolidin-1-one

3-Chloro-2,2-dimethyl-1-(5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)propan-1-one(100 mg, 0.37 mmol) was dissolved in MeOH (4 mL). NaCNBH₃ (35 mg, 0.568mmol) was added followed by two drops of 1N HCl solution and the mixturewas stirred at room temperature for 1 h, then warmed to 60° C. andstirred at that temperature for 5 hours. The solvent was evaporatedunder reduced pressure. The residue was dissolved in EtOAc and washedwith sat. NaHCO₃ solution. The organic phase was dried over Na₂SO₄ andevaporated under reduced pressure. The crude product was purified bycolumn chromatography (cyclohexane/EtOAc, 50:50) to afford2,2-dimethyl-7-phenyl-hexahydropyrazolo[1,2-a]pyrazolidin-1-one (62 mg)as a mixture of enantiomers as a white solid. This mixture was resolvedby chiral HPLC on a Chiralpak IC (25×2.0 cm), 5 μm column using a mobilephase of n-hexane/(EtOH/MeOH 1/1) 50/50% v/v and a flow rate of 18mL/min to afford the title compound as the second eluting enantiomer. ¹HNMR (400 MHz, CDCl₃) δ 7.40-7.19 (m, 5H), 5.05 (t, J=7.8 Hz, 1H), 3.48(br. d, J=9.5 Hz, 1H), 3.35 (br. s, 1H), 2.86 (dddd, J=12.5, 8.7, 6.6,2.5 Hz, 1H), 2.75 (br. d, J=9.3 Hz, 1H), 2.51 (br. s, 1H), 2.33 (tdd,J=6.8, 12.5, 10.2 Hz, 1H), 1.40 (s, 3H), 1.27 (s, 3H). LC-MS (Method A):m/z=231.3 [M+H]⁺, 0.69 min. e.e.>99% as determined on a Chiralpak IC(25×0.46 cm), 5 m column using a mobile phase of n-hexane/(EtOH/MeOH1/1) 50/50% v/v, flow rate: 1 mL/min, retention time: 7.9 min.

Example 22,2-diethyl-7-(4-fluorophenyl)-hexahydropyrazolo[1,2-a]pyrazolidin-1-one

To a solution of ethyl2-ethyl-2-[5-(4-fluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl]butanoate(100 mg, 0.3 mmol) in THF (2.5 mL) at −78° C. was added DIBAL (1Msolution in toluene, 0.3 mL, 0.3 mmol) and the mixture was stirred at−78° C. for 1 h and then at room temperature for 20 h. The reaction wascooled again to −78° C. and DIBAL (1M solution in toluene, 0.3 mL, 0.3mmol) was added, then stirring was continued at room temperature for 5h. The THF was evaporated under reduced pressure, methanol (3 mL) andNaBH₃CN (18 mg, 0.3 mmol) were added. The mixture was stirred at roomtemperature for 1 h then further NaBH₃CN (18 mg, 0.3 mmol) was addedtogether with a drop of 1N HCl solution and the mixture was stirred at60° C. overnight. The mixture was evaporated under reduced pressure, theresidue was diluted with EtOAc and washed with water. The organic phasewas dried over Na₂SO₄ and evaporated under reduced pressure. The crudeproduct was purified by column chromatography (cyclohexane/EtOAc, 50:50)and then by reverse phase column chromatography (water/MeCN, 50:50) toafford the title compound as a racemic mixture. ¹H NMR (400 MHz, CDCl₃)δ 7.35-7.26 (m, 2H), 7.06-6.98 (m, 2H), 5.03 (t, J=7.8 Hz, 1H), 3.48 (d,J=10.3 Hz, 1H), 3.40-3.29 (m, 1H), 2.90-2.77 (m, 2H), 2.54-2.42 (m, 1H),2.33-2.21 (m, 1H), 1.77-1.69 (m, 2H), 1.65 (q, J=7.5 Hz, 2H), 1.02 (t,J=7.4 Hz, 3H), 0.95 (t, J=7.5 Hz, 3H). LC-MS (Method A): m/z=277.2[M+H]⁺, 0.88 min.

Example 37-(3-fluorophenyl)-2,2-dimethyl-hexahydropyrazolo[1,2-a]pyrazolidin-1-one

The title compound was prepared according to Procedure A and the crudeproduct was purified by column chromatography (cyclohexane/EtOAc, 50:50)to afford the racemate as a colorless oil. This mixture was resolved bychiral HPLC on a Chiralpak AD-H (25×2.0 cm), 5 μm column using a mobilephase of n-hexane/(EtOH+0.1% isopropylamine) 70/30% v/v and a flow rateof 18 mL/min to afford the title compound as the second elutingenantiomer. ¹H NMR (400 MHz, CDCl₃) δ 7.34-7.26 (m, 1H), 7.08 (dd,J=7.8, 0.8 Hz, 1H), 7.01 (td, J=2.1, 9.7 Hz, 1H), 6.98-6.91 (m, 1H),5.03 (t, J=7.8 Hz, 1H), 3.48 (br. d, J=9.0 Hz, 1H), 3.40-3.28 (m, 1H),2.86 (dddd, J=12.6, 8.7, 6.7, 2.4 Hz, 1H), 2.74 (d, J=9.3 Hz, 1H),2.57-2.45 (m, 1H), 2.29 (tdd, J=7.0, 12.6, 10.3 Hz, 1H), 1.39 (s, 3H),1.26 (s, 3H). LC-MS (Method A): m/z=249.3 [M+H]⁺, 0.75 min. e.e.>99% asdetermined on a Chiralpak AD-H (25×0.46 cm), 5 μm column using a mobilephase of n-hexane/(EtOH+0.1% isopropylamine) 70/30% v/v, flow rate: 1mL/min, retention time: 8.0 min.

Example 43-[6,6-dimethyl-7-oxo-hexahydropyrazolo[1,2-a]pyrazolidin-1-yl]benzonitrile

The title compound was prepared according to Procedure A and the crudeproduct was purified by column chromatography (cyclohexane:EtOAc, 70:30to 0:100) to afford the racemate. This mixture was resolved by chiralHPLC on a Chiralpak AD-H (25×2.0 cm), 5 μm column using a mobile phaseof n-hexane/EtOH 60/40% v/v and a flow rate of 17 mL/min to afford thetitle compound as the second eluting enantiomer. ¹H NMR (400 MHz,DMSO-d₆) δ 7.75 (td, J=1.8, 7.0 Hz, 1H), 7.71-7.68 (m, 1H), 7.63-7.55(m, 2H), 5.01 (t, J=7.9 Hz, 1H), 3.45-3.35 (m, 1H), 3.31-3.18 (m, 1H),2.93-2.82 (m, 1H), 2.81-2.71 (m, 1H), 2.13-1.99 (m, 1H), 1.23 (s, 3H),1.11 (s, 3H). LC-MS (Method A): m/z=256.3 [M+H]⁺, 0.69 min. e.e.>99% asdetermined on a Chiralpak AD-H (25×0.46 cm), 5 μm column using a mobilephase of n-hexane/EtOH 60/40% v/v, flow rate: 1 mL/min, retention time:9.9 min.

Example 53-[6,6-dimethyl-7-oxo-hexahydropyrazolo[1,2-a]pyrazolidin-1-yl]-5-fluorobenzonitrile

The title compound was prepared according to Procedure A and the crudeproduct was purified by column chromatography (cyclohexane/EtOAc, 50:50to 0:100) to afford the racemate. This mixture was resolved by chiralHPLC on a Chiralpak IC (25×2.0 cm), 5 μm column using a mobile phase ofn-hexane/(EtOH+0.1% isopropylamine) 50/50% v/v and a flow rate of 18mL/min to afford the title compound as the second eluting enantiomer. ¹HNMR (400 MHz, CDCl₃) δ 7.43-7.41 (m, 1H), 7.32-7.25 (m, 2H), 5.04 (t,J=7.5 Hz, 1H), 3.51 (br. d, J=9.8 Hz, 1H), 3.37 (br. t, J=7.4 Hz, 1H),2.90 (dddd, J=12.7, 8.7, 6.7, 2.0 Hz, 1H), 2.79 (br. d, J=9.5 Hz, 1H),2.60-2.49 (m, 1H), 2.26 (tdd, J=7.1, 12.7, 10.3 Hz, 1H), 1.40 (s, 3H),1.28 (s, 3H). LC-MS (Method A): m/z=274.3 [M+H]⁺, 0.74 min. e.e.>99% asdetermined on a Chiralpak IC (25×0.46 cm), 5 μm column using a mobilephase of n-hexane/(EtOH+0.1% isopropylamine) 50/50% v/v, flow rate: 1mL/min, retention time: 8.3 min.

Examples 6 and 72-ethyl-7-(3-fluorophenyl)-2-methyl-hexahydropyrazolo[1,2-a]pyrazolidin-1-ones

Prepared according to Procedure A and purified by column chromatography(cyclohexane/EtOAc, 83:17 to 0:100) to provide a mixture of the fourstereoisomers. This mixture was resolved by chiral HPLC on a ChiralpakAD-H (25×2.0 cm), 5 μm column using a mobile phase of n-hexane/EtOH80/20% v/v and a flow rate of 18 mL/min to afford the two diastereomerictitle compounds as single enantiomers.

2-Ethyl-7-(3-fluorophenyl)-2-methyl-hexahydropyrazolo[1,2-a]pyrazolidin-1-oneas the third eluting stereoisomer (Example 6). ¹H NMR (500 MHz, CDCl₃) δ7.32-7.27 (m, 1H), 7.08 (d, J=7.8 Hz, 1H), 7.01 (dt, J=9.8, 2.0 Hz, 1H),6.94 (td, J=8.2, 2.2 Hz, 1H), 5.04 (t, J=7.8 Hz, 1H), 3.60 (br. d, J=8.3Hz, 1H), 3.33 (br. s, 1H), 2.83 (dddd, J=12.7, 8.6, 6.6, 2.5 Hz, 1H),2.71 (br. d, J=9.8 Hz, 1H), 2.49 (br. s, 1H), 2.26 (ddt, J=12.6, 10.5,7.0 Hz, 1H), 1.81-1.66 (m, 2H), 1.23 (s, 3H), 1.01 (t, J=7.6 Hz, 3H).LC-MS (Method A): m/z=263.8 [M+H]⁺, 0.83 min. e.e.>99% as determined ona Chiralpak AD-H (25×0.46 cm), 5 μm column using a mobile phase ofn-hexane/EtOH 80/20% v/v, flow rate: 1 mL/min, retention time: 8.6 min.2-Ethyl-7-(3-fluorophenyl)-2-methyl-hexahydropyrazolo[1,2-a]pyrazolidin-1-one(Example 7) as the fourth eluting stereoisomer. ¹H NMR (400 MHz, CDCl₃)δ 7.34-7.27 (m, 1H), 7.09 (d, J=7.8 Hz, 1H), 7.03 (td, J=2.0, 9.8 Hz,1H), 6.95 (dt, J=2.0, 8.4 Hz, 1H), 5.03 (t, J=7.6 Hz, 1H), 3.44-3.27 (m,2H), 2.92-2.77 (m, 2H), 2.55-2.43 (m, 1H), 2.36-2.14 (m, 1H), 1.66 (q,J=7.5 Hz, 2H), 1.38 (s, 3H), 0.96 (t, J=7.5 Hz, 3H). LC-MS (Method A):m/z=263.8 [M+H]⁺, 0.83 min. e.e.>99% as determined on a Chiralpak AD-H(25×0.46 cm), 5 μm column using a mobile phase of n-hexane/EtOH 80/20%v/v, flow rate: 1 mL/min, retention time: 9.3 min.

Example 86,6-dimethyl-3-phenyl-hexahydro-1H-pyrazolidino[1,2-a]pyridazin-5-one

Lithium triethylborohydride (1M solution in THF, 2.92 mL, 2.92 mmol) wasadded dropwise at 0° C. to a stirred solution of4-chloro-2,2-dimethyl-1-(5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)butan-1-one(406 mg, 1.46 mmol) in THF (25 mL). The mixture was stirred and allowedto warm to room temperature overnight. Further lithiumtriethylborohydride (1M solution in THF, 0.8 mL, 0.8 mmol) was addeddropwise and the mixture was stirred at room temperature for 1 h. Thevolatiles were evaporated under reduced pressure to give a yellow oil,which was dissolved in EtOAc and washed with sat. KHCO₃ solution andsat. NH₄Cl solution. The organic phase was dried over Na₂SO₄ andevaporated under reduced pressure. The crude product was purified bycolumn chromatography (cyclohexane/EtOAc, 50:50 to 0:100) to afford the6,6-dimethyl-3-phenyl-hexahydro-1H-pyrazolidino[1,2-a]pyridazin-5-one asa racemic mixture isolated as a white solid. This mixture was resolvedby chiral HPLC on a Chiralpak AD-H (25×2.0 cm), 5 μm column using amobile phase of n-hexane/EtOH 65/35% v/v and a flow rate of 17 mL/min toafford the title compound as the second eluting enantiomer as a yellowoil. ¹H NMR (400 MHz, CDCl₃) δ 7.38-7.17 (m, 5H), 5.20 (dd, J=9.0, 6.0Hz, 1H), 3.35-3.23 (m, 2H), 2.91-2.75 (m, 2H), 2.60 (dddd, J=12.5, 9.1,6.7, 4.4 Hz, 1H), 2.10-1.96 (m, 2H), 1.87 (ddd, J=13.8, 6.1, 2.9 Hz,1H), 1.28 (s, 3H), 1.23 (s, 3H). LC-MS (Method A): m/z=245.3 [M+H]⁺,0.78 min. e.e.>99% as determined on a Chiralpak AD-H (25×0.46 cm), 5 μmcolumn using a mobile phase of n-hexane/EtOH 65/35% v/v, flow rate: 1mL/min, retention time: 7.1 min.

Example 93-(3,4-difluorophenyl)-6,6-dimethyl-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one

Prepared according to Procedure A and purified by column chromatography(cyclohexane/EtOAc, 50/50 to 0/100) to afford the title compound. ¹H NMR(400 MHz, CDCl₃) δ 7.19-7.08 (m, 2H), 7.07-7.00 (m, 1H), 4.99 (t, J=7.8Hz, 1H), 3.48 (d, J=9.0 Hz, 1H), 3.40-3.30 (m, 1H), 2.85 (dddd, J=12.6,8.7, 6.7, 2.1 Hz, 1H), 2.75 (d, J=9.5 Hz, 1H), 2.59-2.47 (m, 1H),2.35-2.22 (m, 1H), 1.39 (s, 3H), 1.26 (s, 3H). LC-MS (Method A):m/z=267.2 [M+H]⁺, 0.79 min.

Examples 10 and 113-(3,4-difluorophenyl)-6-ethyl-6-methyl-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one

Prepared according to Procedure A and purified by column chromatography(cyclohexane/EtOAc, 80:20 to 0:100) to give the title compounds as amixture of the four stereoisomers isolated as a yellow oil. This mixturewas resolved by chiral HPLC on a Chiralpak AD-H (25×2.0 cm), 5 μm columnusing a mobile phase of n-hexane/2-propanol 60/40% v/v and a flow rateof 18 mL/min to afford the two diastereomeric title compounds as singleenantiomers.

3-(3,4-Difluorophenyl)-6-ethyl-6-methyl-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-oneas the third eluting stereoisomer (Example 10). ¹H NMR (400 MHz, CDCl₃)δ 7.18-7.08 (m, 2H), 7.07-7.01 (m, 1H), 5.00 (t, J=7.8 Hz, 1H), 3.60 (d,J=9.8 Hz, 1H), 3.34 (t, J=6.8 Hz, 1H), 2.83 (dddd, J=12.7, 8.6, 6.7, 2.1Hz, 1H), 2.73 (d, J=10.0 Hz, 1H), 2.57-2.45 (m, 1H), 2.25 (tdd, J=7.0,12.6, 10.5 Hz, 1H), 1.82-1.65 (m, 2H), 1.24 (s, 3H), 1.02 (t, J=7.5 Hz,3H). LC-MS (Method A): m/z=281.2 [M+H]⁺, 0.88 min. e.e.>99% asdetermined on a Chiralpak AD-H (25×0.46 cm), 5 μm column using a mobilephase of n-hexane/EtOH 80/20% v/v, flow rate: 1 mL/min, retention time:9.7 min.

3-(3,4-Difluorophenyl)-6-ethyl-6-methyl-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-oneas the fourth eluting stereoisomer (Example 11). ¹H NMR (400 MHz, CDCl₃)δ 7.18-7.08 (m, 2H), 7.07-7.01 (m, 1H), 4.98 (t, J=7.8 Hz, 1H),3.43-3.30 (m, 2H), 2.91-2.76 (m, 2H), 2.55-2.43 (m, 1H), 2.28 (tdd,J=7.0, 12.7, 10.3 Hz, 1H), 1.65 (q, J=7.5 Hz, 2H), 1.36 (s, 3H), 0.95(t, J=7.5 Hz, 3H). LC-MS (Method A): m/z=281.2 [M+H]⁺, 0.88 min.e.e.>99% as determined on a Chiralpak AD-H (25×0.46 cm), 5 μm columnusing a mobile phase of n-hexane/EtOH 80/20% v/v, flow rate: 1 mL/min,retention time: 11.8 min.

Example 123-(3-fluorophenyl)-3′,3′-dimethyl-spiro[1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazole-6,1′-cyclobutane]-5-one

1-[1-(Chloromethyl)-3,3-dimethylcyclobutanecarbonyl]-5-(3-fluorophenyl)-4,5-dihydro-1H-pyrazole(65 mg, 0.20 mmol) was dissolved in anhydrous THF (6 mL) and theresulting solution was cooled to 0° C. Super hydride (1M solution inTHF, 0.6 mL, 0.6 mmol) was added dropwise and the mixture was thenstirred at room temperature for 4 h. Another equivalent of Super hydridesolution was added and the mixture was stirred at room temperature for 1h. Sat. NH₄Cl solution was added and the mixture was extracted withEtOAc. The combined organic phases were washed with brine, dried overNa₂SO₄, filtered and evaporated under reduced pressure. The crudeproduct was purified by column chromatography (cyclohexane/EtOAc, 85:15to 20:80) to afford the title compound as a racemic mixture. ¹H NMR (400MHz, CDCl₃) δ 7.35-7.29 (m, 1H), 7.15-7.01 (m, 2H), 6.99-6.88 (m, 1H),5.10-4.99 (m, 1H), 3.78 (d, J=10.3 Hz, 1H), 3.33-3.20 (m, 2H), 2.80-2.67(m, 1H), 2.49-2.33 (m, 3H), 2.27-2.15 (m, 1H), 1.95 (d, J=12.0 Hz, 1H),1.74 (d, J=11.8 Hz, 1H), 1.25-1.17 (m, 6H). LC-MS (Method A): m/z=289.2[M+H]⁺, 1.01 min.

Example 136-(1,1-difluoroethyl)-3-(3-fluorophenyl)-6-methyl-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one

3-(3-fluorophenyl)-2,3,6,7-tetrahydro-1H-pyrazolo[1,2-a]pyrazol-5-one(Procedure B): To a stirring mixture of3-chloro-1-(5-(3-fluorophenyl)-4,5-dihydropyrazol-1-yl) propan-1-one (2g, 7.85 mmol) in acetic acid (50 mL) was added sodium cyanborohydride(1.2 g, 19.1 mmol). The resulting mixture was heated at 90° C., andstirred for 5 hours. After cooling to room temperature, the reactionmixture was concentrated under vacuum, diluted with water (50 mL), thepH value was adjusted to 9 by the addition of aqueous hydrochloric acid(1 N, 50 mL), and extracted with ethyl acetate (3×100 mL). The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography (methane/dichloromethane, 1/10) toafford the title compound (1.5 g, 87%) as a yellow oil. LCMS (Method E):m/z=221.0 [M+H]⁺, 0.577 min.

6-acetyl-3-(3-fluorophenyl)-2,3,6,7-tetrahydro-1H-pyrazolo[1,2-a]pyrazol-5-one:A solution of potassium bis(trimethylsilyl)amide in tetrahydrofuran (1M, 17 mL, 17 mmol) was added to a stirring mixture of3-(3-fluorophenyl)-2,3,6,7-tetrahydro-1H-pyrazolo[1,2-a]pyrazol-5-one(3.0 g, 13.6 mmol) in tetrahydrofuran (70 mL) dropwise at −60° C. Theresulting mixture was stirred at −60° C. for 1 hour followed by theaddition of a solution of methyl acetate (1.2 g, 16.4 mmol) intetrahydrofuran (10 mL) dropwise. After stirring for 1 hour at −60° C.,the reaction mixture was quenched by the addition of saturated aqueousammonium chloride (20 mL) and extracted with ethyl acetate (3×50 mL).The combined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography (ethyl acetate/petroleum ether, 1/3)to afford the title compound as the first eluting racemic diastereomer(1.40 g, 39%) isolated as a yellow oil. LCMS (Method M): m/z=263.0[M+H]⁺, 1.066 min.

6-acetyl-3-(3-fluorophenyl)-6-methyl-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one:To a stirring mixture of6-acetyl-3-(3-fluorophenyl)-2,3,6,7-tetrahydro-1H-pyrazolo[1,2-a]pyrazol-5-one(600 mg, 2.30 mmol) and potassium carbonate (316 mg, 2.30 mmol) inN,N-dimethylformamide (10 mL) was added iodomethane (325 mg, 2.30 mmol)dropwise. After stirring at room temperature for 2 hours, the reactionmixture was quenched by the addition of water (50 mL) and extracted withethyl acetate (3×100 mL). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by column chromatography (ethylacetate/petroleum ether, 3/2) to afford the title compound (150 mg, 24%)as a colorless oil. LC-MS (Method M): m/z=277.1 [M+H]⁺, 1.387 min.

6-(1,1-difluoroethyl)-3-(3-fluorophenyl)-6-methyl-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one:To a stirring mixture of6-acetyl-3-(3-fluorophenyl)-6-methyl-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one(14 mg, 0.05 mmol) in 1,2-dichloroethane (1.0 mL) was addedbis(2-methoxyethyl)aminosulphur trifluoride (23 mg, 0.10 mmol). Theresulting mixture was stirred at 80° C. for 0.5 hour. After cooling toroom temperature, the reaction mixture was quenched by the addition ofwater (20 mL) and extracted with ethyl acetate (3×50 mL). The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by Prep-HPLC with the following conditions: Column: XBridgePrep C18, 5 mm, 30×100 mm; Mobile Phase A: water (0.1% NH₄HCO₃), MobilePhase B: ACN; Flow rate: 20 mL/min; Gradient: 20% B to 50% B over 8.5min; UV 254 & 220 nm Rt: 8.00 min to afford the title compound as thefirst eluting racemic diastereomer. ¹H NMR (400 MHz, CD₃OD) δ 7.39-7.33(m, 1H), 7.14-7.11 (m, 1H), 7.06-6.97 (m, 2H), 5.02 (t, J=8.0 Hz, 1H),3.50-3.47 (m, 1H), 3.42-3.37 (m, 1H), 3.33-3.20 (m, 1H), 3.00-2.91 (m,1H), 2.64-2.56 (m, 1H), 2.30-2.20 (m, 1H), 1.79 (t, J=20.0 Hz, 3H), 1.51(s, 3H). LC-MS (Method E): m/z=299.0 [M+H]⁺, 1.711 min.

Example 146-allyl-3-(3-fluorophenyl)-6-methyl-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one

To a solution of3-(3-fluorophenyl)-6-methyl-2,3,6,7-tetrahydro-1H-pyrazolo[1,2-a]pyrazol-5-one(431 mg, 2.2 mmol) in THF at −78° C. was added DMPU (2 mL) followed byKHMDS solution (0.5M/PhMe, 4.31 mL, 2.2 mmol). The resulting reactionmixture was stirred for 20 min before allyl bromide (285 mg, 2.36 mmol)was added. The reaction mixture was stirred at −78° C. for 1 h. Thereaction mixture was diluted with NH₄Cl solution (15 mL) and EtOAc (15mL). The layers were separated and the aqueous layer was extracted withEtOAc (3×15 mL). The combined organic layers were dried over MgSO₄,filtered, and concentrated under reduced pressure. The crude reactionmixture was purified employing silica gel chromatography (25-90%EtOAc/hexanes) to provide the title compound as the second elutingracemic diastereomer. ¹H-NMR (400 MHz, CDCl₃): δ 7.30 (td, J=8.0, 5.9Hz, 1H), 7.10-7.07 (m, 1H), 7.03-7.00 (m, 1H), 6.98-6.93 (m, 1H),5.85-5.74 (m, 1H), 5.17-5.10 (m, 2H), 5.04-5.00 (m, 1H), 3.36-3.32 (m,2H), 2.89-2.82 (m, 2H), 2.52-2.46 (m, 1H), 2.41 (ddt, J=14.0, 6.7, 1.3Hz, 1H), 2.34-2.25 (m, 2H), 1.40 (s, 3H). LCMS (Method C): m/z=275.59[M+H]⁺.

Example 153-(3-fluorophenyl)-6-methyl-6-propyl-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one

To a solution of6-allyl-3-(3-fluorophenyl)-6-methyl-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one(25 mg, 0.091 mmol) (first eluting racemic diastereomer) in EtOH (2 mL)was added Pd(OH)₂ (2.5 mg, 20 wt %). The solution was stirred under anatmosphere of hydrogen overnight. The reaction mixture was filteredthrough a pad of celite and concentrated under reduced pressure toprovide the title compound as a racemic mixture. ¹H-NMR (400 MHz,CDCl₃): δ 7.33-7.27 (m, 1H), 7.10-7.07 (m, 1H), 7.04-7.00 (m, 1H),6.97-6.92 (m, 1H), 5.04 (t, J=7.8 Hz, 1H), 3.62-3.59 (m, 1H), 3.35-3.31(m, 1H), 2.83 (dddd, J=12.6, 8.7, 6.5, 2.3 Hz, 1H), 2.74-2.71 (m, 1H),2.53-2.46 (m, 1H), 2.27 (ddt, J=12.6, 10.3, 7.0 Hz, 1H), 1.73-1.61 (m,2H), 1.57-1.47 (m, 1H), 1.45-1.34 (m, 1H), 1.25 (s, 3H), 0.97 (t, J=7.3Hz, 3H). LCMS (Method C): m/z=277.50 [M+H]⁺.

Example 163-(3-fluorophenyl)-6-methyl-6-propyl-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one

To a solution of6-allyl-3-(3-fluorophenyl)-6-methyl-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one(3.3 mg, 0.012 mmol) (second eluting racemic diastereomer) in EtOH (1mL) was added Pd(OH)₂ (1 mg, 20 wt %). The solution was stirred under anatmosphere of hydrogen overnight. The reaction mixture was filteredthrough a pad of celite and concentrated under reduced pressure toprovide the title compound as a racemic mixture. ¹H-NMR (400 MHz,CDCl₃): δ 7.31 (td, J=8.0, 5.9 Hz, 1H), 7.10-7.07 (m, 1H), 7.04-7.00 (m,1H), 6.98-6.93 (m, 1H), 5.04-5.00 (m, 1H), 3.42-3.32 (m, 2H), 2.90-2.79(m, 2H), 2.53-2.46 (m, 1H), 2.30 (ddt, J=12.6, 10.2, 6.9 Hz, 1H),1.67-1.45 (m, 4H), 1.38 (s, 3H), 0.98-0.95 (m, 3H).

Example 176-(cyclopropylmethyl)-3-(3-fluorophenyl)-6-methyl-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one

6-(Cyclopropylmethyl)-3-(3-fluorophenyl)-2,3,6,7-tetrahydro-1H-pyrazolo[1,2-a]pyrazol-5-one(16.0 mg, 0.06 mmol) and DMPU (0.4 mL, 0.06 mmol) were treated withKHMDS solution (0.5M/PhMe, 0.13 mL, 0.06 mmol) in THF at −78° C. Thereaction mixture was stirred for 30 min, MeI (60.0 μL, 0.09 mmol) wasadded and the reaction was warmed to 0° C. The reaction mixture wastreated with NH₄Cl solution (10 mL) and EtOAc (10 mL) The layers wereseparated and the aqueous layer was extracted with EtOAc (3×10 mL). Thecombined organic layers were dried over anhydrous MgSO₄, filtered, andconcentrated under reduced pressure. The crude reaction mixture waspurified employing silica gel column chromatography (0-80%EtOAc/hexanes) to provide the desired product as a racemic mixture.¹H-NMR (400 MHz, CDCl₃): δ 7.33-7.28 (m, 1H), 7.10-7.07 (m, 1H),7.04-7.00 (m, 1H), 6.95 (tdd, J=8.5, 2.6, 0.9 Hz, 1H), 5.05-5.01 (m,1H), 3.49-3.47 (m, 1H), 3.39-3.34 (m, 1H), 3.03-3.01 (m, 1H), 2.86(dddd, J=12.7, 8.6, 6.5, 2.2 Hz, 1H), 2.55-2.48 (m, 1H), 2.30 (ddt,J=12.6, 10.4, 7.0 Hz, 1H), 1.63-1.48 (m, 2H), 1.44 (s, 3H), 0.74-0.65(m, 1H), 0.57-0.52 (m, 1H), 0.49-0.44 (m, 1H), 0.15-0.08 (m, 2H). LCMS(Method C): m/z=289.1 [M+H]⁺.

Example 183-(5-bromo-3-pyridyl)-6-(difluoromethyl)-6-ethyl-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one

1-(5-(5-bromopyridin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)-2-(chloromethyl)-2-(difluoromethyl)butan-1-one:Synthesized according to Preparation 6 and purified by silica gel columnchromatography (PE:EtOAc=1:1) to provide the title compound (0.33 g,13.19%) as a light yellow oil.

3-(5-bromo-3-pyridyl)-6-(difluoromethyl)-6-ethyl-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one:Prepared according to Procedure B. The crude reaction mixture waspurified employing reverse-phase HPLC to provide the title compound asthe first eluting diastereomer isolated as a mixture of enantiomers.¹H-NMR (400 MHz CDCl₃): δ 8.59 (d, J=2.2 Hz, 1H), 8.50 (d, J=1.9 Hz,1H), 7.78 (t, J=2.1 Hz, 1H), 5.95 (t, J=56.3 Hz, 1H), 5.06 (t, J=8.0 Hz,1H), 3.57-3.54 (m, 1H), 3.43-3.34 (m, 2H), 2.85 (dddd, J=12.6, 8.7, 6.8,1.2 Hz, 1H), 2.62-2.55 (m, 1H), 2.24 (ddt, J=12.6, 11.2, 7.2 Hz, 1H),1.90 (dq, J=14.2, 7.2 Hz, 1H), 1.78-1.69 (m, 1H), 1.09 (t, J=7.5 Hz,3H). LCMS (Method C): m/z=360.1, 362.1 [M+H]⁺.

Example 195-(6-(difluoromethyl)-6-ethyl-5-oxo-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-3-yl)pyridine-3-carbonitrileProcedure C

To a flask containing3-(5-bromo-3-pyridyl)-6-(difluoromethyl)-6-ethyl-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one(38.0 mg, 0.11 mmol) (first eluting diastereomer as a mixture ofenantiomers), and Zn(CN)₂ (12.4 mg, 0.11 mmol) was added DMF (1.0 mL).The suspension was sparged with argon for 15 min before Pd(PPh₃)₄(24.4mg, 0.02 mmol) was added. The resulting reaction mixture was heated at100° C. overnight. The reaction mixture was diluted with EtOAc (20 mL)and filtered through celite. The filtrate was treated with NH₄Clsolution (10 mL). The layers were separated and the aqueous layer wasextracted with EtOAc (3×10 mL). The combined organic layers were driedover anhydrous MgSO₄, filtered, and concentrated under reduced pressure.The crude reaction mixture was purified employing reverse-phase HPLC toprovide the title product as a mixture of enantiomers. ¹H-NMR (400 MHz,CDCl₃): δ 8.83-8.80 (m, 2H), 7.94-7.93 (m, 1H), 5.97 (dd, J=56.6, 56.0Hz, 1H), 5.14 (dd, J=8.3, 7.9 Hz, 1H), 3.59 (dd, J=12.1, 2.1 Hz, 1H),3.47 (d, J=12.1 Hz, 1H), 3.42-3.38 (m, 1H), 2.91 (dddd, J=12.6, 8.8,6.7, 1.2 Hz, 1H), 2.68-2.61 (m, 1H), 2.29-2.20 (m, 1H), 1.96-1.87 (m,1H), 1.81-1.71 (m, 1H), 1.10 (t, J=7.5 Hz, 3H). LCMS (Method C):m/z=307.13 [M+H]⁺.

Example 206-(difluoromethyl)-6-ethyl-3-(3-fluorophenyl))-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one

Methyl6-ethyl-3-(3-fluorophenyl)-5-oxo-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazole-6-carboxylate:Prepared according to Procedure B to provide the title compound as acolorless oil. LCMS (Method C): m/z=307.3 [M+H]⁺.

6-ethyl-3-(3-fluorophenyl)-6-(hydroxymethyl)-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one:Lithium chloride (21.7 mg, 0.50 mmol) and sodium borohydride (37.8 mg,1.0 mmol) were added to a solution of methyl6-ethyl-3-(3-fluorophenyl)-5-oxo-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazole-6-carboxylate(153 mg, 0.50 mmol) in THF (5 mL) and Ethanol (5 mL) at 0° C. Thereaction mixture was stirred at 0° C. for 3 h. The reaction was quenchedby adding 10 mL of water then extracted with ethyl acetate (20 mL×3).The organics were collected and dried over MgSO₄ before concentratingunder reduced pressure. The resulting residue was purified by flashchromatography (0-100% ethyl acetate in hexanes) to yield the titlecompound as a colorless oil (49 mg, 0.18 mmol, 35.2%). LCMS (Method C):m/z=279.3 [M+H]⁺.

6-ethyl-3-(3-fluorophenyl)-5-oxo-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazole-6-carbaldehyde:Dess-Martin periodinane (68.6 mg, 0.16 mmol) was added to a solution of6-ethyl-3-(3-fluorophenyl)-6-(hydroxymethyl)-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one(30 mg, 0.11 mmol) in DCM (3 mL). The reaction mixture was stirred at rtfor 1 h before adding sodium thiosulfate solution (2.0 M, 2 mL). Themixture was extracted with ethyl acetate (10 mL×2) and the organiclayers were collected and washed with water (10 mL) and brine (20 mL)before concentrating under reduced pressure to provide the titlecompound as a colorless oil (5 mg, 30%). LCMS (Method C): m/z=277.3[M+H]⁺.

6-(difluoromethyl)-6-ethyl-3-(3-fluorophenyl)-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one:Deoxy-fluor (0.07 mL, 0.41 mmol) was added to a solution of6-ethyl-3-(3-fluorophenyl)-5-oxo-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazole-6-carbaldehyde(56 mg, 0.20 mmol) in DCE (5 mL). The reaction mixture was sealed andstirred at 80° C. for 1 h. The reaction mixture was diluted with 5%aqueous NaHCO₃ solution (25 mL) and EtOAc (50 mL). The organic layer wascollected and washed with water (25 mL) and brine (25 mL), dried overanhydrous MgSO₄, filtered and concentrated under reduced pressure. Thecrude product was purified using flash chromatography (0-80% ethylacetate in hexanes) to provide the title compound as a racemic mixtureisolated as a yellow oil. This mixture was resolved by chiral HPLC on aChiralpak IA (25×2.0 cm), 5 μm column using a mobile phase ofn-hexane/ethanol 75/25% v/v and a flow rate of 17 mL/min to afford thetitle compound as the second eluting enantiomer. ¹H NMR (400 MHz, CDCl₃)δ 7.35-7.29 (m, 1H), 7.12-7.08 (m, 1H), 7.07-7.01 (m, 1H), 6.97 (dt,J=2.8, 8.4 Hz, 1H), 5.97 (t, J=56.7 Hz, 1H), 5.07 (t, J=8.0 Hz, 1H),3.56 (dd, J=11.8, 2.0 Hz, 1H), 3.40 (d, J=11.8 Hz, 1H), 3.35 (t, J=7.7Hz, 1H), 2.83 (td, J=7.5, 12.6 Hz, 1H), 2.62-2.53 (m, 1H), 2.27 (tt,J=11.8, 7.2 Hz, 1H), 1.98-1.87 (m, 1H), 1.76 (qd, J=7.3, 14.2 Hz, 1H),1.13 (t, J=7.4 Hz, 3H). LC-MS (Method A): m/z=299.5 [M+H]⁺, 597.4[2M+H]⁺, 0.99 min. e.e.>99% as determined on a Chiralpak IA (25×0.46cm), 5 μm column using a mobile phase of n-hexane/ethanol 75/25% v/v,flow rate: 1.0 mL/min, retention time: 10.3 min.

Examples 21 and 223-(3,5-difluorophenyl)-6-ethyl-6-methyl-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one

Prepared according to Procedure A to give the title compounds as amixture of the four stereoisomers. This mixture was resolved by chiralHPLC on a Chiralpak AD-H (25×2.0 cm), 5 μm column using a mobile phaseof n-hexane/ethanol 85/15% v/v and a flow rate of 17 mL/min to affordthe two diastereomeric title compounds as single enantiomers.

3-(3,5-difluorophenyl)-6-ethyl-6-methyl-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-oneas the third eluting stereoisomer (Example 21). ¹H NMR (400 MHz, CDCl₃)δ 6.89-6.81 (m, 2H), 6.70 (tt, J=8.9, 2.3 Hz, 1H), 5.05-4.99 (m, 1H),3.61 (d, J=10.0 Hz, 1H), 3.38-3.30 (m, 1H), 2.84 (dddd, J=12.7, 8.7,6.7, 2.1 Hz, 1H), 2.74 (d, J=10.0 Hz, 1H), 2.56-2.45 (m, 1H), 2.25 (tdd,J=7.0, 12.6, 10.4 Hz, 1H), 1.84-1.68 (m, 2H), 1.25 (s, 3H), 1.03 (t,J=7.5 Hz, 3H). LC-MS (Method B): m/z=281.2 [M+H]⁺, 561.4 [2M+H]⁺, 0.92min. e.e.>99% as determined on a Chiralpak AD-H (25×0.46 cm), 5 μmcolumn using a mobile phase of n-hexane/ethanol 85/15% v/v, flow rate:1.0 mL/min, retention time: 9.9 min.

3-(3,5-difluorophenyl)-6-ethyl-6-methyl-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-oneas the fourth eluting stereoisomer (Example 22). ¹H NMR (400 MHz, CDCl₃)δ 6.88-6.80 (m, 2H), 6.70 (tt, J=8.9, 2.3 Hz, 1H), 5.03-4.95 (m, 1H),3.42-3.31 (m, 2H), 2.90-2.78 (m, 2H), 2.54-2.44 (m, 1H), 2.27 (tdd,J=6.9, 12.7, 10.4 Hz, 1H), 1.65 (q, J=7.5 Hz, 2H), 1.38 (s, 3H), 0.96(t, J=7.5 Hz, 3H). LC-MS (Method B): m/z=281.2 [M+H]⁺, 561.4 [2M+H]⁺,0.91 min. e.e.>99% as determined on a Chiralpak AD-H (25×0.46 cm), 5 μmcolumn using a mobile phase of n-hexane/ethanol 85/15% v/v, flow rate:1.0 mL/min, retention time: 11.3 min.

Examples 23 and 243-fluoro-5-(6-ethyl-6-methyl-5-oxo-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-3-yl)benzonitrile

Prepared according to Procedure A to give the title compounds as amixture of the four stereoisomers. This mixture was resolved by chiralHPLC on a Chiralpak AD-H (25×2.0 cm), 5 μm column using a mobile phaseof n-hexane/ethanol 55/45% v/v and a flow rate of 17 mL/min to affordthe two diastereomeric title compounds as single enantiomers.

3-fluoro-5-(6-ethyl-6-methyl-5-oxo-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-3-yl)benzonitrileas the third eluting stereoisomer (Example 23). ¹H NMR (400 MHz, CDCl₃)δ 7.43 (s, 1H), 7.33-7.24 (m, 2H), 5.06 (t, J=7.9 Hz, 1H), 3.63 (d,J=10.0 Hz, 1H), 3.42-3.29 (m, 1H), 2.94-2.82 (m, 1H), 2.77 (d, J=10.3Hz, 1H), 2.61-2.48 (m, 1H), 2.23 (tdd, J=7.0, 12.6, 10.5 Hz, 1H),1.83-1.66 (m, 2H), 1.26 (s, 3H), 1.03 (t, J=7.5 Hz, 3H). LC-MS (MethodA): m/z=288.2 [M+H]⁺, 0.86 min. e.e.>99% as determined on a ChiralpakAD-H (25×0.46 cm), 5 m column using a mobile phase of n-hexane/ethanol55/45% v/v, flow rate: 1.0 mL/min, retention time: 8.5 min.

3-fluoro-5-(6-ethyl-6-methyl-5-oxo-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-3-yl)benzonitrileas the fourth eluting stereoisomer (Example 24). ¹H NMR (400 MHz, CDCl₃)δ 7.42 (s, 1H), 7.32-7.24 (m, 2H), 5.07-5.00 (m, 1H), 3.46-3.32 (m, 2H),2.95-2.80 (m, 2H), 2.58-2.47 (m, 1H), 2.26 (tdd, J=7.0, 12.7, 10.4 Hz,1H), 1.66 (q, J=7.5 Hz, 2H), 1.38 (s, 3H), 0.96 (t, J=7.5 Hz, 3H). LC-MS(Method A): m/z=288.2 [M+H]⁺, 0.86 min. e.e.>99% as determined on aChiralpak AD-H (25×0.46 cm), 5 Cpm column using a mobile phase ofn-hexane/ethanol 55/45% v/v, flow rate: 1.0 mL/min, retention time: 9.9min.

Examples 25 and 266-ethyl-3-(5-fluoro-3-pyridyl)-6-methyl-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one

Prepared according to Procedure A to give the title compounds as amixture of the four stereoisomers. This mixture was resolved by chiralSFC on a Chiralpak AD-H (25×2.0 cm), 5 μm column using a mobile phase of12% methanol in CO₂ and a flow rate of 45 mL/min to afford the twodiastereomeric title compounds as single enantiomers.

6-ethyl-3-(5-fluoro-3-pyridyl)-6-methyl-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-oneas the third eluting stereoisomer (Example 25). ¹H NMR (400 MHz, CDCl₃)δ 8.44-8.41 (m, 1H), 8.40 (d, J=2.8 Hz, 1H), 7.39 (td, J=2.1, 9.1 Hz,1H), 5.11 (t, J=7.9 Hz, 1H), 3.62 (d, J=9.8 Hz, 1H), 3.42-3.33 (m, 1H),2.90 (dddd, J=12.7, 8.8, 6.7, 2.0 Hz, 1H), 2.77 (d, J=10.3 Hz, 1H),2.60-2.47 (m, 1H), 2.29 (tdd, J=7.0, 12.7, 10.4 Hz, 1H), 1.83-1.65 (m,2H), 1.26 (s, 3H), 1.02 (t, J=7.5 Hz, 3H). LC-MS (Method A): m/z=264.2[M+H]⁺, 0.63 min. e.e.>99% as determined on a Chiralpak AD-H (25×0.46cm), 5 μm column using a mobile phase of n-hexane/ethanol 75/25% v/v,flow rate: 1.0 mL/min, retention time: 22.6 min.

6-ethyl-3-(5-fluoro-3-pyridyl)-6-methyl-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-oneas the fourth eluting stereoisomer (Example 26). ¹H NMR (400 MHz, CDCl₃)δ 8.42 (t, J=1.6 Hz, 1H), 8.40 (d, J=2.8 Hz, 1H), 7.38 (td, J=2.0, 9.0Hz, 1H), 5.13-5.04 (m, 1H), 3.40 (d, J=10.0 Hz, 2H), 2.92 (dddd, J=12.7,8.7, 6.6, 2.1 Hz, 1H), 2.84 (d, J=9.8 Hz, 1H), 2.59-2.48 (m, 1H), 2.32(tdd, J=7.0, 12.8, 10.3 Hz, 1H), 1.66 (q, J=7.5 Hz, 2H), 1.37 (s, 3H),0.96 (t, J=7.5 Hz, 3H). LC-MS (Method A): m/z=264.2 [M+H]⁺, 0.63 min.e.e.>99% as determined on a Chiralpak AD-H (25×0.46 cm), 5 μm columnusing a mobile phase of n-hexane/ethanol 75/25% v/v, flow rate: 1.0mL/min, retention time: 31.3 min.

Example 276-(2,2-difluoroethyl)-3-(3-fluorophenyl)-6-methyl-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one

6-allyl-3-(3-fluorophenyl)-2,3,6,7-tetrahydro-1H-pyrazolo[1,2-a]pyrazol-5-one:To a stirring mixture of3-(3-fluorophenyl)-2,3,6,7-tetrahydro-1H-pyrazolo[1,2-a]pyrazol-5-one(9.3 g, 42.3 mmol) in tetrahydrofuran (150 mL) was added a solution ofpotassium bis(trimethylsilyl)amide in tetrahydrofuran (1 M, 42.3 mL,42.3 mmol) dropwise at −60° C. The resulting mixture was stirred for 1hour at −60° C. followed by the addition of a solution of allyl bromide(5.12 g, 42.3 mmol) in tetrahydrofuran (20 mL) dropwise. After stirringfor 1 hour at −60° C., the reaction mixture was quenched by the additionof saturated aqueous ammonium chloride (50 mL) and extracted with ethylacetate (3×50 mL). The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated undervacuum. The residue was purified by column chromatography (ethylacetate/petroleum ether, 1/3) to afford the title compound (2.3 g, 21%)as a yellow oil. LCMS (Method D): m/z=261.2 [M+H]⁺, 0.886 min.

6-allyl-3-(3-fluorophenyl)-6-methyl-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one:To a stirring mixture of6-allyl-3-(3-fluorophenyl)-2,3,6,7-tetrahydro-1H-pyrazolo[1,2-a]pyrazol-5-one(2.3 g, 8.85 mmol) in tetrahydrofuran (50 mL) at −60° C. was added asolution of potassium bis(trimethylsilyl)amide in tetrahydrofuran (1 M,8.85 mL, 8.85 mmol) dropwise. The resulting mixture was stirred for 1hour at −60° C., and followed by the addition of a solution ofiodomethane (1.26 g, 8.85 mmol) in tetrahydrofuran (5 mL) dropwise.After stirring for 1 hour at −60° C., the reaction mixture was quenchedby the addition of saturated aqueous ammonium chloride (20 mL) andextracted with ethyl acetate (3×30 mL). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by columnchromatography (ethyl acetate/petroleum ether, 1/3) to afford the titlecompound (1.65 g, 68%) as a racemic mixture isolated as a yellow oil.LCMS (Method D): m/z=275.2 [M+H]⁺, 0.955 min.

2-[3-(3-fluorophenyl)-6-methyl-5-oxo-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-6-yl]acetaldehyde:To a stirring mixture of6-allyl-3-(3-fluorophenyl)-6-methyl-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one(1.70 g, 6.20 mmol) in 1,4-dioxane (30 mL) and water (10 mL) were addedosmium tetraoxide (16 mg, 0.06 mmol) and sodium periodate (2.66 g, 12.4mmol). After stirring for 2 hours at room temperature, the reactionmixture was diluted with water (20 mL) and extracted with ethyl acetate(3×30 mL). The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated under vacuum.The residue was purified by column chromatography (ethylacetate/petroleum ether, 1/4) to afford the title compound as a racemicmixture isolates as a yellow oil (800 mg, 47%). LCMS (Method D):m/z=277.2 [M+H]⁺, 0.761 min.

6-(2,2-difluoroethyl)-3-(3-fluorophenyl)-6-methyl-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one:To a stirring mixture of2-[3-(3-fluorophenyl)-6-methyl-5-oxo-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-6-yl]acetaldehyde(200 mg, 0.72 mmol) in dichloromethane (1 mL) was addedBis(2-methoxyethyl)aminosulfur trifluoride (1.59 g, 7.20 mmol). Afterstirring for 0.5 hour at room temperature, the reaction mixture wasquenched by the addition of water (20 mL) and extracted with ethylacetate (3×30 mL). The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated undervacuum. The residue was purified by Prep-HPLC with the followingconditions: Column: XBridge Prep C18, 5 μm, 19×150 mm; Mobile Phase A:water (0.1% NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 20 mL/min;Gradient: 22% B to 55% B over 8 min; UV 254 & 220 nm; Rt: 7.78 min toafford the title compound as a racemic mixture. ¹H NMR (400 MHz, CD₃OD)δ 7.40-7.32 (m, 1H), 7.15-7.10 (m, 1H), 7.06-6.96 (m, 2H), 6.30-5.97 (m,1H), 5.01 (t, J=8.0 Hz, 1H), 3.53 (d, J=9.6 Hz, 1H), 3.46-3.34 (m, 1H),3.02-2.87 (m, 2H), 2.65-2.51 (m, 1H), 2.33-1.99 (m, 3H), 1.43 (s, 3H).LC-MS (Method J): m/z=299.0 [M+H]⁺, 1.238 min.

Example 282-(3-(3-fluorophenyl)-6-methyl-5-oxo-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-6-yl)acetonitrile

2-[3-(3-fluorophenyl)-6-methyl-5-oxo-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-6-yl]acetaldehydeoxime: Hydroxylamine hydrochloride (45 mg, 0.65 mmol) was added to amixture of2-[3-(3-fluorophenyl)-6-methyl-5-oxo-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-6-yl]acetaldehyde(150 mg, 0.54 mmol) in acetonitrile (8 mL). The resulting mixture wasstirred for 1 hour at 70° C. After cooling to room temperature, thereaction mixture was quenched by the addition of water (20 mL) andextracted with ethyl acetate (3×20 mL). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, and filtered.The filtrate was concentrated under vacuum to afford the title compound(125 mg crude) as a yellow oil. LCMS (Method K): m/z=292.15 [M+H]⁺,0.842 min.

2-[3-(3-fluorophenyl)-6-methyl-5-oxo-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-6-yl]acetonitrile:Trifluoroacetic anhydride (451 mg, 2.15 mmol) was added to a mixture of2-(7-(3-fluorophenyl)-2-methyl-1-oxo-hexahydropyrazolo[1,2-a]pyrazol-2-yl)acetaldehydeoxime (125 mg, 0.43 mmol) in dichloromethane (6 mL). After stirring for4 hours at 40° C., the reaction mixture was quenched by the addition ofwater (20 mL) and extracted with dichloromethane (3×20 mL). The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography (ethyl acetate/petroleum ether, 2/1)to afford the racemate as a yellow oil. LCMS (Method F): m/z=274.25[M+H]⁺, 0.721 min. The racemate was separated by Prep-Chiral-HPLC withthe following conditions: Column: CHIRALPAK IG UL001, 20×250 mm, 5 μm;Mobile Phase A: Hexane, Mobile Phase B: EtOH; Flow rate: 20 mL/min;Gradient: 50% B to 50% B over 20 min; UV 254 & 220 nm; Rt: 17.149 min toafford the title compound as the second eluting enantiomer. ¹H NMR (300MHz, Methanol-d₄) δ 7.39 (td, J=7.9, 5.8 Hz, 1H), 7.18-7.10 (m, 1H),7.11-6.99 (m, 2H), 5.04 (t, J=7.9 Hz, 1H), 3.62 (d, J=9.5 Hz, 1H), 3.45(t, J=7.9 Hz, 1H), 3.07-2.92 (m, 2H), 2.87-2.69 (m, 2H), 2.67-2.54 (m,1H), 2.36-2.19 (m, 1H), 1.46 (s, 3H). LC-MS (Method I): m/z=274.1[M+H]⁺, 1.129 min.

Example 296-(chloromethyl)-6-ethyl-3-(3-fluorophenyl)-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one

[6-ethyl-3-(3-fluorophenyl)-5-oxo-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-6-yl]methyltrifluoromethanesulfonate: Trifluoromethanesulfonic anhydride (55.8 mg,0.20 mmol) and pyridine (17.1 mg, 0.22 mmol) were added to solution of6-ethyl-3-(3-fluorophenyl)-6-(hydroxymethyl)-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one(50 mg, 0.18 mmol) in DCM (2 mL). The reaction mixture was stirred at rtovernight. The reaction mixture was concentrated to dryness and theresidue was taken up in EtOAc (25 mL), washed with 2×10 mL water and1×10 mL saturated brine solution. The organics were separated and driedover MgSO₄ before concentrating under reduced pressure. The resultingresidue was purified by flash column chromatography eluting with 25%EtOAc in hexanes to yield the title compound as a racemic mixtureisolated as a colorless solid (15 mg, 21%). LCMS (Method C): m/z=411.3[M+H]⁺.

6-(chloromethyl)-6-ethyl-3-(3-fluorophenyl)-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one:LiCl (8.5 mg, 0.2 mmol) was added to a solution of[6-ethyl-3-(3-fluorophenyl)-5-oxo-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-6-yl]methyltrifluoromethanesulfonate (44 mg, 0.11 mmol) in DCM (2 mL). The reactionmixture was stirred at rt for 3 h and then concentrated to dryness. Theresulting residue was taken up in EtOAc (25 mL) and washed with 2×20 mLwater and 1×25 mL saturated brine solution. The organics were thenseparated and dried over MgSO₄ before concentrating to dryness. Thecrude material was purified by flash column chromatography eluting with50% EtOAc in hexanes to yield the title compound as a racemic mixture.¹H-NMR (400 MHz; CDCl₃): δ 7.35-7.31 (m, 1H), 7.15-7.13 (m, 1H),7.08-7.05 (m, 1H), 7.00-6.97 (m, 1H), 5.10-5.06 (m, 1H), 3.84 (d, J=11.3Hz, 1H), 3.70-3.65 (m, 1H), 3.54 (d, J=11.3 Hz, 1H), 3.49-3.43 (m, 1H),3.31-3.27 (m, 1H), 2.91-2.83 (m, 1H), 2.73-2.68 (m, 1H), 2.38-2.31 (m,1H), 1.90-1.79 (m, 2H), 1.11 (t, J=7.5 Hz, 3H). LCMS (Method C):m/z=297.1, 299.1 [M+H]⁺.

Example 306-Ethyl-6-(fluoromethyl)-3-(3-fluorophenyl)-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one

TBABF (36 mg, 0.13 mmol) was added to a solution of[6-ethyl-3-(3-fluorophenyl)-5-oxo-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-6-yl]methyltrifluoromethanesulfonate (44 mg, 0.11 mmol) in DCM (2 mL). The reactionmixture was stirred at rt for 3 h and then concentrated to dryness. Theresulting residue was taken up in EtOAc (25 mL) and washed with 2×20 mLwater and 1×25 mL saturated brine solution. The organics were separatedand dried over MgSO₄ before concentrating to dryness. The crude productwas purified by flash column chromatography eluting with 50% EtOAc inhexanes to provide the title compound as a racemic mixture. ¹H-NMR (400MHz; CDCl₃): δ 7.32 (dt, J=8.0, 4.0 Hz, 1H), 7.13-7.10 (m, 1H),7.07-7.03 (m, 1H), 6.99-6.93 (m, 1H), 5.10-5.06 (m, 1H), 4.69 (dd,J=47.1, 9.2 Hz, 1H), 4.31-4.17 (m, 1H), 3.72-3.63 (m, 1H), 3.41-3.35 (m,1H), 3.28-3.23 (m, 1H), 2.87-2.80 (m, 1H), 2.63-2.56 (m, 1H), 2.37-2.22(m, 1H), 1.75-1.60 (m, 2H), 1.12-1.05 (m, 3H). LCMS (Method C):m/z=281.1, [M+H]⁺.

Examples 31 and 323-fluoro-5-(6-(difluoromethyl)-6-ethyl-5-oxo-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-3-yl)benzonitrile

Prepared according to Procedure B and purified by flash chromatographyto provide the two diastereomeric title compounds.

3-Fluoro-5-(6-(difluoromethyl)-6-ethyl-5-oxo-1,2,3,7-tetrahydropyrazlo[1,2-a]pyrazol-3-yl)benzonitrileas the first eluting diastereomer (Example 31). ¹H-NMR (400 MHz; CDCl₃):δ 7.43 (td, J=1.3, 0.3 Hz, 1H), 7.31-7.29 (m, 2H), 5.96 (dd, J=56.6,56.1 Hz, 1H), 5.07 (dd, J=8.2, 7.9 Hz, 1H), 3.59-3.42 (m, 2H), 3.36 (t,J=7.8 Hz, 1H), 2.87 (dddd, J=12.6, 8.8, 6.7, 1.2 Hz, 1H), 2.60 (dddd,J=11.1, 8.4, 6.9, 1.5 Hz, 1H), 2.21 (ddt, J=12.5, 11.2, 7.2 Hz, 1H),1.92 (dq, J=14.3, 7.2 Hz, 1H), 1.76 (ddd, J=13.9, 7.5, 1.2 Hz, 1H), 1.12(t, J=7.5 Hz, 3H). LCMS (Method C): m/z=324.3 [M+H]⁺. e.e.=90%.

3-Fluoro-5-(6-(difluoromethyl)-6-ethyl-5-oxo-1,2,3,7-tetrahydropyrazlo[1,2-a]pyrazol-3-yl)benzonitrileas the second eluting diastereomer (Example 32). ¹H-NMR (400 MHz;CDCl₃): δ 7.41 (t, J=1.3 Hz, 1H), 7.30-7.29 (m, 1H), 7.28-7.27 (m, 1H),6.08-5.80 (m, 1H), 5.07-5.03 (m, 1H), 3.97 (d, J=11.3 Hz, 1H), 3.40-3.35(m, 1H), 3.00-2.91 (m, 2H), 2.61-2.55 (m, 1H), 2.28 (ddt, J=12.7, 10.1,6.9 Hz, 1H), 1.93-1.85 (m, 1H), 1.77-1.67 (m, 2H), 1.06 (t, J=7.5 Hz,3H). LCMS (Method C): m/z=324.3 [M+H]⁺. e.e.=90%.

Examples 33 and 346-(difluoromethyl)-6-ethyl-3-(5-fluoro-3-pyridyl)-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one

Prepared according to Procedure B and purified by flash chromatography(0-70% ethyl acetate in hexanes) to provide the two diastereomeric titlecompounds.

6-(Difluoromethyl)-6-ethyl-3-(5-fluoro-3-pyridyl)-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-oneas the second eluting diastereomer isolated as a mixture of enantiomers(Example 33). ¹H-NMR (400 MHz; CDCl₃): δ 8.43-8.42 (m, 1H), 8.41 (d,J=2.8 Hz, 1H), 7.39 (dddd, J=9.1, 2.7, 1.9, 0.7 Hz, 1H), 5.97 (t, J=56.3Hz, 1H), 5.15-5.11 (m, 1H), 3.55 (d, J=2.1 Hz, 1H), 3.44 (d, J=11.9 Hz,1H), 3.38 (t, J=7.7 Hz, 1H), 2.88 (dddd, J=12.6, 8.8, 6.7, 1.2 Hz, 1H),2.64-2.57 (m, 1H), 2.32-2.22 (m, 1H), 1.91 (dt, J=14.1, 7.2 Hz, 1H),1.75 (ddd, J=14.4, 7.0, 1.2 Hz, 1H), 1.11 (t, J=7.5 Hz, 3H). LCMS(Method C): m/z=300.1 [M+H]⁺.

6-(Difluoromethyl)-6-ethyl-3-(5-fluoro-3-pyridyl)-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-oneas the first eluting diastereomer isolated as a mixture of enantiomers(Example 34). ¹H-NMR (400 MHz; CDCl₃): δ 8.40 (dd, J=4.6, 2.2 Hz, 2H),7.39 (dddd, J=9.1, 2.6, 1.9, 0.7 Hz, 1H), 5.93 (t, J=55.9 Hz, 1H),5.11-5.08 (m, 1H), 3.95 (dd, J=11.1, 0.5 Hz, 1H), 3.38-3.33 (m, 1H),3.00-2.92 (m, 2H), 2.63-2.56 (m, 1H), 2.32 (ddt, J=12.7, 9.8, 6.8 Hz,1H), 1.89 (dt, J=14.5, 7.3 Hz, 1H), 1.75-1.71 (m, 1H), 1.06 (t, J=7.5Hz, 3H). LCMS (Method C): m/z=300.1 [M+H]⁺.

Example 353-fluoro-5-(6-(cyclopropylmethyl)-6-methyl-5-oxo-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-3-yl)benzonitrile

Prepared according to Procedure B and purified by flash chromatography(0-70% ethyl acetate in hexanes) to provide the title compound as thefirst eluting diastereomer (a racemic mixture of a single diastereomer).¹H-NMR (400 MHz; CDCl₃): δ 7.41 (t, J=1.3 Hz, 1H), 7.30-7.29 (m, 1H),7.28-7.27 (m, 1H), 5.00-5.05 (m, 1H), 3.45-3.49 (m, 1H), 3.38-3.36 (m,1H), 3.03-3.00 (m, 1H), 2.90-2.80 (m, 1H), 2.52-2.48 (m, 1H), 2.34-2.28(m, 1H), 1.60-1.40 (m, 2H), 1.46 (s, 3H), 0.70-0.60 (m, 1H), 0.55-0.45(m, 2H), 0.20-0.10 (m, 2H). LCMS (Method C): m/z=314.3 [M+H]⁺.

Examples 36, 37, 38 and 395-[6-(1,1-difluoroethyl)-6-methyl-5-oxo-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-3-yl]pyridine-3-carbonitrileand5-[6-(difluoromethyl)-6-methyl-5-oxo-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-3-yl]pyridine-3-carbonitrile

3-(5-bromo-3-pyridyl)-6-(1,1-difluoroethyl)-6-methyl-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-oneand3-(5-bromo-3-pyridyl)-6-(difluoromethyl)-6-methyl-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one:Prepared according to Procedure B to give a mixture of3-(5-bromo-3-pyridyl)-6-(1,1-difluoroethyl)-6-methyl-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one.LC-MS (Method O): m/z=360.1 362.1 [M+H]⁺, 1.180 min and3-(5-bromo-3-pyridyl)-6-(difluoromethyl)-6-methyl-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one.LC-MS (Method O): m/z=346.1, 348.1 [M+H]⁺, 1.133 min as a light yellowoil. The crude residue was used without purification in the next step.

5-[6-(1,1-difluoroethyl)-6-methyl-5-oxo-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-3-yl]pyridine-3-carbonitrileand5-[6-(difluoromethyl)-6-methyl-5-oxo-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-3-yl]pyridine-3-carbonitrile:Prepared according to Procedure C and purified by Prep-HPLC with thefollowing conditions: column: Agela Durashell C18 150 mm×25 mm 5 μm;mobile phase A: water (10 mM NH₄HCO₃), mobile phase B: ACN; 10%-35% Bover 10.5 min to provide the title compounds, which were furtherpurified by Prep-TLC (SiO₂, PE:EtOAc=1:1) to yield pure products.

5-[6-(1,1-difluoroethyl)-6-methyl-5-oxo-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-3-yl]pyridine-3-carbonitrileas the second eluting product (89% ee). This compound was furtherpurified by SFC with the following conditions: Instrument: Thar SFC80preparative SFC; Column: Chiralpak AD-H 250 mm×30 mm i.d. 5 μm; Mobilephase A: CO₂ Mobile phase B: MeOH (0.1% NH₃H₂O); Gradient: B %=30%; Flowrate: 65 g/min; Wavelength: 220 nm; Column temperature: 40° C.; Systemback pressure: 100 bar to provide the first eluting isomer as a singleenantiomer (Example 36). ¹H NMR (400 MHz, CDCl₃): δ 8.81 (d, J=1.9 Hz,1H), 8.77 (d, J=2.1 Hz, 1H), 7.90 (t, J=2.0 Hz, 1H), 5.10 (t, J=7.8 Hz,1H), 4.16 (br d, J=10.2 Hz, 1H), 3.41 (br s, 1H), 3.01-2.84 (m, 2H),2.59 (br s, 1H), 2.33-2.22 (m, 1H), 1.76 (t, J=19.5 Hz, 3H), 1.44 (s,3H). LC-MS (Method N): m/z=307.3 [M+H]⁺, 1.235 min.

5-[6-(1,1-difluoroethyl)-6-methyl-5-oxo-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-3-yl]pyridine-3-carbonitrileas the fourth eluting product (89% ee). This compound was furtherpurified by SFC with the following conditions: Instrument: Thar SFC80preparative SFC; Column: Chiralpak AD-H 250 mm×30 mm i.d. 5 μm; Mobilephase A: CO₂ Mobile phase B: MeOH (0.1% NH₃H₂O); Gradient: B %=40%; Flowrate: 70 g/min; Wavelength: 220 nm; Column temperature: 40° C.; Systemback pressure: 100 bar to afford the second eluting isomer as a singleenantiomer (Example 37). ¹H NMR (400 MHz, CDCl₃): δ 8.80 (d, J=1.9 Hz,1H), 8.77 (d, J=2.1 Hz, 1H), 7.91 (t, J=2.0 Hz, 1H), 5.09 (t, J=8.0 Hz,1H), 3.49 (s, 2H), 3.37 (t, J=7.8 Hz, 1H), 2.92 (dddd, J=12.7, 8.5, 6.9,1.1 Hz, 1H), 2.70-2.62 (m, 1H), 2.27 (tdd, J=12.6, 10.9, 7.2 Hz, 1H),1.84 (t, J=20.0 Hz, 3H), 1.52 (s, 3H). LC-MS (Method N): m/z=307.3[M+H]⁺, 1.291 min.

5-[6-(difluoromethyl)-6-methyl-5-oxo-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-3-yl]pyridine-3-carbonitrileas the first eluting product (88% ee) (Example 38). ¹H NMR (400 MHz,CDCl₃) δ 8.81 (d, J=2.0 Hz, 1H), 8.77 (s, 1H), 7.91 (t, J=2.1 Hz, 1H),5.87 (t, J=56 Hz, 1H), 5.06-5.15 (m, 1H), 4.06 (br d, J=11.3 Hz, 1H),3.41 (br s, 1H), 2.97 (dddd, J=12.8, 8.8, 6.7, 2.1 Hz, 1H), 2.90 (br d,J=11.7 Hz, 1H), 2.60 (br s, 1H), 2.24-2.34 (m, 1H), 1.42 (s, 3H). LC-MS(Method N): m/z=293.3 [M+H]⁺, 1.154 min.

5-[6-(difluoromethyl)-6-methyl-5-oxo-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-3-yl]pyridine-3-carbonitrileas the third eluting product (85% ee) (Example 39). ¹H NMR (400 MHz,CDCl₃) δ 8.82 (d, J=2.0 Hz, 1H), 8.78 (d, J=2.0 Hz, 1H), 7.93 (t, J=1.9Hz, 1H), 5.92 (t, J=56 Hz, 1H), 5.10 (t, J=8.0 Hz, 1H), 3.42-3.57 (m,2H), 3.37 (t, J=7.8 Hz, 1H), 2.84-2.98 (m, 1H), 2.58-2.71 (m, 1H), 2.25(tdd, J=12.7, 11.0, 7.1 Hz, 1H), 1.51 (s, 3H). LC-MS (Method N):m/z=293.3 [M+H]⁺, 1.208 min.

Examples 40, 41, 42 and 433-[6-(1,1-difluoroethyl)-6-methyl-5-oxo-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-3-yl]-5-fluoro-benzonitrileand3-[6-(difluoromethyl)-6-methyl-5-oxo-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-3-yl]-5-fluoro-benzonitrile

Prepared according to Procedure B and purified by Prep-TLC (SiO₂,PE:EtOAc=1:1) followed by purification by Prep-HPLC with the followingconditions: column: Agela Durashell C18 150 mm×25 mm 5 μm; mobile phase:[A: water (0.1% TFA)—B: ACN]; Flow rate: 25 mL/min; Gradient: B %20%-50% over 10.5 min to afford the title compounds.

3-[6-(difluoromethyl)-6-methyl-5-oxo-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-3-yl]-5-fluoro-benzonitrileas the first eluting product (76% ee) (Example 40). ¹H NMR (400 MHz,CDCl₃) δ 7.42 (s, 1H), 7.29 (s, 1H), 7.27-7.28 (m, 1H), 5.92 (t, J=56.4Hz, 1H), 5.03 (t, J=7.9 Hz, 1H), 3.40-3.54 (m, 2H), 3.35 (t, J=7.8 Hz,1H), 2.87 (dddd, J=12.6, 8.6, 7.0, 1.3 Hz, 1H), 2.56-2.65 (m, 1H), 2.23(tdd, J=12.6, 11.1, 7.3 Hz, 1H), 1.51 (s, 3H). LC-MS (Method N):m/z=310.3 [M+H]⁺, 1.420 min.

3-[6-(difluoromethyl)-6-methyl-5-oxo-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-3-yl]-5-fluoro-benzonitrileas the second eluting product (78% ee) (Example 41). ¹H NMR (400 MHz,CDCl₃) δ 7.40 (s, 1H), 7.29 (s, 1H), 7.27 (d, J=1.1 Hz, 1H), 5.89 (t,J=56 Hz, 1H), 5.00-5.08 (m, 1H), 4.05 (br d, J=11.3 Hz, 1H), 3.38 (br s,1H), 2.81-3.00 (m, 2H), 2.56 (br d, J=7.1 Hz, 1H), 2.20-2.33 (m, 1H),1.41 (s, 3H). LC-MS (Method N): m/z=310.3 [M+H]⁺, 1.362 min.

3-[6-(1,1-difluoroethyl)-6-methyl-5-oxo-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-3-yl]-5-fluoro-benzonitrileas the third eluting product. This compound was further purified by SFC(column: IC (250 mm×30 mm, 10 μm); Mobile phase A: CO₂; Mobile phase B:MeOH; B %: 10%-10% over 10 min) to provide the second eluting isomer(Rt=5.5 min) as a single enantiomer (Example 42). ¹H NMR (400 MHz,CDCl₃) δ 7.41 (s, 1H), 7.28 (d, J=0.9 Hz, 1H), 7.26 (d, J=1.3 Hz, 1H),5.03 (t, J=8.0 Hz, 1H), 3.42-3.52 (m, 2H), 3.35 (t, J=7.8 Hz, 1H), 2.88(dddd, J=12.7, 8.5, 6.9, 1.3 Hz, 1H), 2.62 (td, J=10.7, 7.8 Hz, 1H),2.24 (tdd, J=12.6, 11.0, 7.2 Hz, 1H), 1.85 (t, J=20.0 Hz, 3H), 1.53 (s,3H). LC-MS (Method N): m/z=324.3 [M+H]⁺, 1.499 min.

3-[6-(1,1-difluoroethyl)-6-methyl-5-oxo-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-3-yl]-5-fluoro-benzonitrileas the fourth eluting product. Further purification by SFC (column: AD(250 mm×30 mm, 5 μm); Mobile phase A: CO₂; Mobile phase B: MeOH; B %:15%-15% over 10 min) provided the second eluting isomer (Rt=8 min) as asingle enantiomer (Example 43). ¹H NMR (400 MHz, CDCl₃) δ 7.40 (s, 1H),7.23-7.30 (m, 2H), 5.04 (t, J=7.9 Hz, 1H), 4.14 (br d, J=11.5 Hz, 1H),3.38 (br s, 1H), 2.79-2.98 (m, 2H), 2.46-2.62 (m, 1H), 2.18-2.32 (m,1H), 1.76 (t, J=19.5 Hz, 3H), 1.44 (s, 3H). LC-MS (Method N): m/z=324.3[M+H]⁺, 1.422 min.

Example 445-(6-(difluoromethyl)-6-ethyl-7-oxohexahydropyrazolo[1,2-a]pyrazol-1-yl)nicotinonitrile

1-(5-(5-bromopyridin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)-2-(chloromethyl)-2-(difluoromethyl)butan-1-one:To a solution of 3-bromo-5-[4,5-dihydro-1H-pyrazol-5-yl]pyridine (1.43g, 6.34 mmol) in THF (15 mL) was added DIPEA (1.64 g, 12.68 mmol) and asolution of 2-(chloromethyl)-2-(difluoromethyl)butanoyl chloride (1.3 g,6.34 mmol) in THF (10 mL) at 0° C. under N₂. The reaction solution wasstirred at 25° C. for 2 h. The mixture was poured into water (60 mL).The aqueous phase was extracted with EtOAc (3×20 mL). The combinedorganic phase was washed with brine (20 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (PE:EtOAc=1:1) to give1-(5-(5-bromopyridin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)-2-(chloromethyl)-2-(difluoromethyl)butan-1-one(the first eluting racemic diastereomer) and1-(5-(5-bromopyridin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)-2-(chloromethyl)-2-(difluoromethyl)butan-1-one(the second eluting racemic diastereomer). LCMS (Method N): m/z=394.1,396.0 [M+H]⁺, 1.308 min.

7-(5-bromopyridin-3-yl)-2-(difluoromethyl)-2-ethyltetrahydropyrazolo[1,2-a]pyrazol-1(5H)-one:Prepared from1-(5-(5-bromopyridin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)-2-(chloromethyl)-2-(difluoromethyl)butan-1-one(the first eluting racemic diastereomer) (330 mg, 836.20 μmol) usingProcedure B and purified by silica gel column chromatography(PE:EtOAc=5:1 to 1:1) to provide the title compound. LCMS (Method O):m/z=360.1, 362.1 [M+H]⁺, 1.145 min.

5-(6-(difluoromethyl)-6-ethyl-7-oxohexahydropyrazolo[1,2-a]pyrazol-1-yl)nicotinonitrile:Prepared according to Procedure C and purified by prep-HPLC with thefollowing conditions: column: Nano-micro Kromasil C18 100 mm×30 mm 5 μm;Mobile phase A: water (0.1% TFA); Mobile phase B: ACN; B %: 20%-45% Bover 10 min followed by neutralization. Further purification by SFC withthe following conditions: Instrument: Thar SFC80 preparative SFC;Column: Chiralpak AS-H 250 mm×30 mm i.d. 5 μm; Mobile phase A: CO₂;Mobile phase B: MeOH; Gradient: B %=20%; Flow rate: 55 g/min;Wavelength: 220 nm; Column temperature: 40° C.; System back pressure:100 bar provided the title compound as a single enantiomer (secondeluting enantiomer). ¹H NMR (400 MHz, CDCl₃): δ 8.81 (d, J=2.01 Hz, 1H),8.78 (d, J=2.3 Hz, 1H), 7.91 (t, J=2.0 Hz, 1H), 5.81-6.13 (m, 1H), 5.12(t, J=8.0 Hz, 1H), 3.54-3.62 (m, 1H), 3.42-3.48 (m, 1H), 3.37 (t, J=7.8Hz, 1H), 2.90 (dt, J=12.7, 7.3 Hz, 1H), 2.57-2.67 (m, 1H), 2.22 (tt,J=11.9, 7.3 Hz, 1H), 1.85-1.96 (m, 1H), 1.74 (dq, J=14.3, 7.1 Hz, 1H),1.09 (t, J=7.5 Hz, 3H). LCMS (Method N): m/z=307.3 [M+H]⁺, 1.264 min.

Examples 45, 46 and 476-(1,1-difluoroethyl)-3-(5-fluoro-3-pyridyl)-6-methyl-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one,and6-(difluoromethyl)-3-(5-fluoro-3-pyridyl)-6-methyl-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one

Prepared according to procedure B and purified by Prep-HPLC with thefollowing conditions: Column: Agela Durashell C18 150 mm×25 mm 5 μm;mobile phase A: water (10 mM NH₄HCO₃) mobile phase B: ACN; Flow rate: 25mL/min; B %: 15%-35% over 10.5 min to give four product peaks, whichwere further purified by prep-TLC (SiO₂, PE:EtOAC=1:1) to give pureproduct.

6-(difluoromethyl)-3-(5-fluoro-3-pyridyl)-6-methyl-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-onewas obtained as the second eluting product (Example 45). ¹H NMR (400MHz, CDCl₃) δ 8.36-8.46 (m, 2H), 7.38 (td, J=9.0, 2.1 Hz, 1H), 5.92 (t,J=56 Hz, 1H), 5.09 (t, J=7.9 Hz, 1H), 3.39-3.56 (m, 2H), 3.36 (br t,J=7.7 Hz, 1H), 2.83-2.94 (m, 1H), 2.55-2.67 (m, 1H), 2.29 (tdd, J=12.6,11.0, 7.1 Hz, 1H), 1.50 (m, 3H). LC-MS (Method N): m/z=286.3 [M+H]⁺,1.195 min.

6-(1,1-difluoroethyl)-3-(5-fluoro-3-pyridyl)-6-methyl-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-onewas obtained as the third eluting product. Further purification by SFC(column: IC-H (250 mm×30 mm i.d., 5 μm); Mobile phase A: CO₂; Mobilephase B: MeOH; B %: 20%-20% over 10 min) provided the first elutingisomer as a single enantiomer (Example 46). ¹H NMR (400 MHz, CDCl₃) δ8.39 (d, J=2.8 Hz, 2H), 7.37 (td, J=9.1, 2.1 Hz, 1H), 5.09 (br t, J=7.8Hz, 1H), 4.13 (br d, J=8.2 Hz, 1H), 3.38 (br s, 1H), 2.78-2.98 (m, 2H),2.56 (br s, 1H), 2.24-2.37 (m, 1H), 1.76 (t, J=19.5 Hz, 3H), 1.44 (s,2H), 1.440 (m, 1H). LC-MS (Method N): m/z=300.3 [M+H]⁺, 1.182 min.

6-(1,1-difluoroethyl)-3-(5-fluoro-3-pyridyl)-6-methyl-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-onewas obtained as the fourth eluting product and was further purified bySFC (Column: Chiralpak AD-H 250 mm×30 mm i.d. 5 μm; Mobile phase A: CO₂;Mobile phase B: MeOH; Gradient: B %=20%-20% over 10 mim) to provide thefirst eluting isomer as a single enantiomer (Example 47). ¹H NMR (400MHz, CDCl₃) δ 8.34-8.45 (m, 2H), 7.37 (td, J=9.0, 2.1 Hz, 1H), 5.07 (t,J=8.0 Hz, 1H), 3.40-3.51 (m, 2H), 3.36 (br t, J=7.7 Hz, 1H), 2.89 (dddd,J=12.7, 8.5, 6.9, 1.4 Hz, 1H), 2.57-2.68 (m, 1H), 2.30 (tdd, J=12.7,10.9, 7.2 Hz, 1H), 1.85 (t, J=20.0 Hz, 3H), 1.51 (s, 3H). LC-MS (MethodN): m/z=300.3 [M+H]⁺, 1.247 min.

Examples 48, 49, 50 and 516-(difluoromethyl)-3-(5-fluoro-3-pyridyl)-6-(2,2,2-trifluoroethyl)-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-oneand3-(5-fluoro-3-pyridyl)-6-methyl-6-(2,2,2-trifluoroethyl)-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one

Prepared according to Procedure B and purified by prep-HPLC using thefollowing conditions: column: Agela Durashell C18 150 mm×25 mm 5 μm;mobile phase A: water (10 mM NH₄HCO₃) mobile phase B: ACN; B %: 25%-45%over 10.5 min to provide the title compounds.

6-(difluoromethyl)-3-(5-fluoro-3-pyridyl)-6-(2,2,2-trifluoroethyl)-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-oneas the fourth eluting product (82% ee) (Example 48). ¹H NMR (400 MHz,CDCl₃) δ 8.45-8.35 (m, 2H), 7.42-7.31 (m, 1H), 5.81-6.19 (t, J=56 Hz,1H), 5.11 (t, J=8.0 Hz, 1H), 3.82 (br d, J=1 1.8 Hz, 1H), 3.44 (br d,J=11.8 Hz, 1H), 3.39 (br t, J=7.2 Hz, 1H), 2.97-2.88 (m, 1H), 2.78-2.71(m, 1H), 2.71-2.65 (m, 1H), 2.65-2.58 (m, 1H), 2.39-2.27 (m, 1H). LCMS(Method N): m/z=354.3 [M+H]⁺, 1.371 min.

6-(difluoromethyl)-3-(5-fluoro-3-pyridyl)-6-(2,2,2-trifluoroethyl)-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-oneas the third eluting product (Example 49). ¹H NMR (400 MHz, CDCl₃) δ8.45-8.36 (m, 2H), 7.36 (td, J=8.9, 2.1 Hz, 1H), 6.16-5.84 (t, J=56 Hz,1H), 5.11 (t, J=7.8 Hz, 1H), 4.01 (d, J=11.7 Hz, 1H), 3.44 (br t, J=7.2Hz, 1H), 3.20 (br d, J=11.7 Hz, 1H), 3.03-2.91 (m, 1H), 2.85-2.65 (m,2H), 2.64-2.56 (m, 1H), 2.42-2.30 (m, 1H). LCMS (Method N): m/z=354.3[M+H]⁺, 1.351 min.

3-(5-fluoro-3-pyridyl)-6-methyl-6-(2,2,2-trifluoroethyl)-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-oneas the second eluting product (79% ee) (Example 50). ¹H NMR (400 MHz,CDCl₃) δ 8.40 (d, J=2.4 Hz, 2H), 7.35 (td, J=9.0, 2.2 Hz, 1H), 5.05 (t,J=7.9 Hz, 1H), 3.64 (br d, J=9.5 Hz, 1H), 3.45 (br t, J=7.4 Hz, 1H),2.94 (dddd, J=12.7, 8.4, 6.5, 1.8 Hz, 1H), 2.86 (br d, J=9.5 Hz, 1H),2.58-2.68 (m, 1H), 2.47-2.57 (m, 1H), 2.30-2.45 (m, 2H), 1.50 (s, 3H).LCMS (Method N): m/z=318.3 [M+H]⁺, 1.318 min.

3-(5-fluoro-3-pyridyl)-6-methyl-6-(2,2,2-trifluoroethyl)-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-oneas the first eluting product (Example 51). ¹H NMR (400 MHz, CDCl₃) δ8.36-8.44 (m, 2H), 7.35 (td, J=9.0, 2.1 Hz, 1H), 5.04 (br t, J=7.5 Hz,1H), 3.73 (br s, 1H), 3.29 (br s, 1H), 2.82-3.01 (m, 2H), 2.71 (br s,1H), 2.39-2.62 (m, 2H), 2.33 (tdd, J=12.9, 8.9, 6.6 Hz, 1H), 1.40 (d,J=0.9 Hz, 3H). LCMS (Method N): m/z=318.3 [M+H]⁺, 1.283 min.

Examples 52 and 536-(cyclopropylmethyl)-6-(difluoromethyl)-3-(5-fluoro-3-pyridyl)-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one

Prepared according to Preparation 6 and purified by prep-TLC (SiO₂,PE:EtOAc=1:1) to provide2-(chloromethyl)-2-(cyclopropylmethyl)-3,3-difluoro-1-[3-(5-fluoro-3-pyridyl)-3,4-dihydropyrazol-2-yl]propan-1-oneas the faster eluting isomer (0.2 g, 15%) as a yellow oil, LC-MS (MethodO): m/z=360.2 [M+H]⁺, 1.299 min and2-(chloromethyl)-2-(cyclopropylmethyl)-3,3-difluoro-1-[3-(5-fluoro-3-pyridyl)-3,4-dihydropyrazol-2-yl]propan-1-oneas the slower eluting isomer (0.27 g, 21%) as a yellow oil, LC-MS(Method O): m/z=360.2 [M+H]⁺, 1.272 min.

6-(cyclopropylmethyl)-6-(difluoromethyl)-3-(5-fluoro-3-pyridyl)-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one:Prepared from2-(chloromethyl)-2-(cyclopropylmethyl)-3,3-difluoro-1-[3-(5-fluoro-3-pyridyl)-3,4-dihydropyrazol-2-yl]propan-1-one(faster eluting isomer) according to Procedure B and purified byprep-TLC (SiO₂, PE:EtOAc=1:3) to provide the title compound (97% ee)(Example 52). ¹H NMR (400 MHz, CDCl₃) δ 8.46-8.35 (m, 2H), 7.40 (td,J=9.1, 2.1 Hz, 1H), 6.17-5.85 (t, J=56 Hz, 1H), 5.13 (t, J=8.0 Hz, 1H),3.72 (dd, J=11.7, 2.0 Hz, 1H), 3.43 (d, J=11.7 Hz, 1H), 3.37 (t, J=7.8Hz, 1H), 2.92-2.83 (m, 1H), 2.66-2.57 (m, 1H), 2.33-2.22 (m, 1H), 1.92(dd, J=14.2, 5.4 Hz, 1H), 1.55-1.46 (m, 1H), 0.97-0.86 (m, 1H),0.63-0.45 (m, 2H), 0.23-0.10 (m, 2H). LC-MS (Method N): m/z=326.3[M+H]⁺, 1.407 min.

6-(cyclopropylmethyl)-6-(difluoromethyl)-3-(5-fluoro-3-pyridyl)-1,2,3,7-tetrahydropyrazolo[1,2-a]pyrazol-5-one:Prepared from2-(chloromethyl)-2-(cyclopropylmethyl)-3,3-difluoro-1-[3-(5-fluoro-3-pyridyl)-3,4-dihydropyrazol-2-yl]propan-1-one(slower eluting isomer) according to Procedure B and purified byprep-TLC (SiO₂, EtOAc) to provide the title compound (94% ee) (Example53). ¹H NMR (400 MHz, CDCl₃) δ 8.39 (d, J=2.4 Hz, 2H), 7.38 (td, J=9.1,2.1 Hz, 1H), 6.13-5.80 (t, J=56 Hz, 1H), 5.14-5.06 (m, 1H), 3.96 (br d,J=11.4 Hz, 1H), 3.25 (d, J=11.3 Hz, 1H), 2.94 (dddd, J=12.8, 8.9, 6.7,2.3 Hz, 1H), 2.64 (br d, J=7.4 Hz, 1H), 2.38-2.25 (m, 1H), 1.83-1.74 (m,1H), 1.83-1.58 (m, 2H), 0.88-0.75 (m, 1H), 0.65-0.48 (m, 2H), 0.28-0.12(m, 2H). LC-MS (Method N): m/z=326.3 [M+H]⁺, 1.353 min.

Example 545-(6-(difluoromethyl)-7-oxo-6-propylhexahydropyrazolo[1,2-a]pyrazol-1-yl)nicotinonitrile

2-allyl-7-(5-bromopyridin-3-yl)-2-(difluoromethyl)tetrahydropyrazolo[1,2-a]pyrazol-1(5H)-one:Prepared from1-[3-(5-bromo-3-pyridyl)-3,4-dihydropyrazol-2-yl]-2-(chloromethyl)-2-(difluoromethyl)pent-4-en-1-one(1 g, 2.46 mmol) using Procedure B and purified by silica gel columnchromatography (PE:EtOAc=1:1) to provide the title compound (0.6 g, 66%)as a yellow oil.

5-(6-allyl-6-(difluoromethyl)-7-oxohexahydropyrazolo[1,2-a]pyrazol-1-yl)nicotinonitrile:Prepared from2-allyl-7-(5-bromopyridin-3-yl)-2-(difluoromethyl)tetrahydropyrazolo[1,2-a]pyrazol-1(5H)-oneusing Procedure C and purified by silica gel column chromatography(PE:EtOAc=1:1 to 0:1) to provide the title compound as a light yellowsolid.

5-(6-(difluoromethyl)-7-oxo-6-propylhexahydropyrazolo[1,2-a]pyrazol-1-yl)nicotinonitrile:To a solution of5-(6-allyl-6-(difluoromethyl)-7-oxohexahydropyrazolo[1,2-a]pyrazol-1-yl)nicotinonitrile(400 mg, 402.11 umol) in EtOAc (5 mL) was added 10% Pd/C (43 mg) in oneportion at 25° C. The mixture was stirred for 2 h under H₂ at 15 psi.The mixture was filtered through a pad of celite. The filtrate wasconcentrated under vacuum. The residue was purified by prep-HPLC withthe following conditions: column: Waters Xbridge 150 mm×25 mm 5 μm;Mobile phase A: water (0.05% HCl); Mobile phase B: ACN; B %: 20%-40%over 12 min to provide the title compound as a mixture of enantiomers.¹H NMR (400 MHz, CDCl₃): δ 8.79 (d, J=1.8 Hz, 1H), 8.77 (d, J=2.0 Hz,1H), 7.93-7.87 (m, 1H), 6.08-5.76 (t, J=56 Hz, 1H), 5.10 (t, J=8.0 Hz,1H), 3.56 (dd, J=12.1, 2.0 Hz, 1H), 3.46-3.40 (m, 1H), 3.35 (t, J=7.8Hz, 1H), 2.92-2.83 (m, 1H), 2.65-2.55 (m, 1H), 2.21 (m, 1H), 1.84-1.73(m, 1H), 1.68-1.54 (m, 2H), 1.41-1.26 (m, 1H), 0.98 (t, J=7.3 Hz, 3H).HPLC (Method T): Retention Time: 2.049 min, m/z=321.2 [M+H]⁺.

Examples 55 and 56(8R)-2-(difluoromethyl)-2-ethyl-5-(3-fluorophenyl)-5,6,7,8-tetrahydro-1H-pyrrolizin-3-one

(5R)-5-but-3-enyl-1-(p-tolylsulfonyl)pyrrolidin-2-one: LiHMDS (1M inmethyl tert-butyl ether) (39.51 mL, 39.51 mmol) was added to a solutionof (5R)-5-but-3-enylpyrrolidin-2-one (5 g, 35.92 mmol) in THF (100 mL)at −20° C. The reaction mixture was stirred at −20° C. for 30 min beforep-toluenesulfonyl chloride (7.53 g, 39.51 mmol) was added. The reactionmixture was stirred at rt overnight. The reaction mixture wasconcentrated to dryness and the residue was taken up in EtOAc (100 mL).The organic layer was washed with 2×50 mL water then 1×50 mL saturatedbrine solution. The organics were then separated and dried (MgSO₄)before concentration to dryness. The crude was then purified by flashcolumn chromatography eluting with 0-100% EtOAc in hexane. The desiredfractions were concentrated to dryness in vacuo. ¹H-NMR (400 MHz;CDCl₃): δ 7.97 (d, J=8.4 Hz, 2H), 7.35 (dd, J=8.6, 0.6 Hz, 2H), 5.83(ddt, J=17.0, 10.4, 6.5 Hz, 1H), 5.09-5.03 (m, 2H), 4.46-4.41 (m, 1H),2.55 (ddd, J=17.7, 11.2, 9.1 Hz, 1H), 2.37 (ddd, J=17.7, 9.5, 2.3 Hz,1H), 2.25-2.09 (m, 4H), 1.93-1.86 (m, 1H), 1.79-1.74 (m, 1H). LCMS(Method C): m/z=294.4 [M+H]⁺, 1.98 min.

(5R)-5-but-3-enyl-3-ethyl-1-(p-tolylsulfonyl)pyrrolidin-2-one: LiHMDS(1M in methyl tert-butyl ether) (22.25 mL, 22.25 mmol) was added to asolution of (5R)-5-but-3-enyl-1-(p-tolylsulfonyl)pyrrolidin-2-one (6.1g, 20.79 mmol) in THF (100 mL) and DMPU (2.53 mL, 20.79 mmol). Thereaction mixture was stirred at −78° C. for 90 min. before ethyltrifluoromethanesulfonate (3.5 mL, 27.03 mmol) was added. The reactionmixture was stirred at −78° C. for 1 h before warming to rt and stirringfor 2 h. The reaction mixture was poured carefully into 100 mL ofice-water. The mixture was extracted with EtOAc (100 mL) and theorganics were washed with 2×50 mL water and 1×100 mL saturated brinesolution. The organics were dried (MgSO₄) before concentration todryness. The crude was then purified by flash column chromatographyeluting with 60% EtOAc in hexane. The desired fractions wereconcentrated to dryness in vacuo. LC-MS (Method C): m/z=322.4 [M+H]⁺,1.92 min.

(5R)-5-but-3-enyl-3-[difluoro(trimethylsilyl)methyl]-3-ethyl-1-(p-tolylsulfonyl)pyrrolidin-2-one:To a solution of(5R)-5-but-3-enyl-3-ethyl-1-(p-tolylsulfonyl)pyrrolidin-2-one (2.3 g,7.16 mmol) in THF (100 mL) was added a solution of LiHMDS (1M in methyltert-butyl ether) (7.3 mL, 7.3 mmol) at −78° C. The reaction mixture wasstirred at 0° C. for 30 min then cooled to −78° C. Methyl lithium (1.6 Min diethyl ether) (4.47 mL, 7.16 mmol) was added and the mixture wasstirred at −78° C. for 10 min before trimethyl(trifluoromethyl)silane(5.29 mL, 35.78 mmol) was added. The reaction mixture was warmed to rtand stirred at rt for 18 h. The reaction mixture was poured carefullyinto ice-water (100 mL) and then extracted with EtOAc (150 mL). Theorganic layer was separated and washed with water (2×100 mL) thensaturated brine solution (1×150 mL). The organics were then separatedand dried over MgSO₄ before concentration to dryness. The crude was thenpurified by flash column chromatography eluting with 20% EtOAc inheptanes. The desired fractions were concentrated to dryness in vacuo.LC-MS (Method C): m/z=444.4 [M+H]⁺, 2.32 min.

3-[(2R)-4-[difluoro(trimethylsilyl)methyl]-4-ethyl-5-oxo-1-(p-tolylsulfonyl)pyrrolidin-2-yl]propanal:Ozone was bubbled through a cooled (−78° C.) solution of(5R)-5-but-3-enyl-3-[difluoro(trimethylsilyl)methyl]-3-ethyl-1-(p-tolylsulfonyl)pyrrolidin-2-one(2.5 g, 5.64 mmol) in DCM (100 mL) until a light blue color appeared.Oxygen was then bubbled through the solution for 10 min followed byargon for 30 min. Triphenylphosphine (2.22 g, 8.45 mmol) was added andthe mixture was stirred at rt for 3 h. The reaction mixture wasconcentrated and purified by flash chromatography to yield the titlecompound (1.3 g, 2.92 mmol, 52% yield). LC-MS (Method C): m/z=446.4[M+H]⁺, 2.01 min.

(5R)-3-[difluoro(trimethylsilyl)methyl]-3-ethyl-5-[3-(3-fluorophenyl)-3-hydroxy-propyl]-1-(p-tolylsulfonyl)pyrrolidin-2-one:3-Fluorophenylmagnesium chloride in THF solution (0.57 mL, 0.57 mmol)was added to a solution of3-[(2R)-4-[difluoro(trimethylsilyl)methyl]-4-ethyl-5-oxo-1-(p-tolylsulfonyl)pyrrolidin-2-yl]propanal(240 mg, 0.54 mmol) in DCM (20 mL). The reaction mixture was stirred atrt overnight before quenching by adding 5 mL of 1.0 N HCl. The reactionmixture was taken up in 50 mL of ethyl acetate, washed with water andbrine and then dried over MgSO₄ before concentration in vacuo. The crudeproduct was purified by flash chromatography to yield the title compound(110 mg, 37.7% yield). LC-MS (Method C): m/z=542.4 [M+H]⁺, 1.95 min.

(5R)-3-[difluoro(trimethylsilyl)methyl]-3-ethyl-5-[3-(3-fluorophenyl)-3-hydroxy-propyl]pyrrolidin-2-one:To a solution of(5R)-3-[difluoro(trimethylsilyl)methyl]-3-ethyl-5-[3-(3-fluorophenyl)-3-hydroxy-propyl]-1-(p-tolylsulfonyl)pyrrolidin-2-one(40 mg, 0.07 mmol) in THF (5 mL) at 0° C. was added a solution of SmI₂(0.1 M, 3.69 mL, 0.37 mmol). The reaction mixture was stirred at 0° C.for 10 min then quenched by adding water (10 mL). The mixture was takenup in ethyl acetate (50 mL) then washed with water (50 mL) and brine (50mL). The organic layer was collected and dried over MgSO₄ beforeconcentration. The crude product was purified by flash chromatography toprovide the title compound (22.5 mg, 78.6%). LC-MS (Method C): m/z=388.4[M+H]⁺, 1.92 min.

[3-[(2R)-4-[difluoro(trimethylsilyl)methyl]-4-ethyl-5-oxo-pyrrolidin-2-yl]-1-(3-fluorophenyl)propyl]methanesulfonate:To a solution of(5R)-3-[difluoro(trimethylsilyl)methyl]-3-ethyl-5-[3-(3-fluorophenyl)-3-hydroxy-propyl]pyrrolidin-2-one(46 mg, 0.12 mmol) in DCM (5 mL) at −10° C. was added triethylamine(0.02 mL, 0.18 mmol) followed by methanesulfonyl chloride (0.01 mL, 0.14mmol). The mixture was stirred at −10° C. for 30 min, concentrated andused directly in the next step. LC-MS (Method C): m/z=466.4 [M+H]⁺, 2.15min.

(8R)-2-(difluoromethyl)-2-ethyl-5-(3-fluorophenyl)-5,6,7,8-tetrahydro-1H-pyrrolizin-3-one:Potassium tert-butoxide (72.3 mg, 0.54 mmol) was added to a solution of[3-[(2R)-4-[difluoro(trimethylsilyl)methyl]-4-ethyl-5-oxo-pyrrolidin-2-yl]-1-(3-fluorophenyl)propyl]methanesulfonate(30 mg, 0.056 mmol) in ethanol (2 mL). The reaction mixture was stirredat 80° C. for 1 h heated by microwave. The reaction mixture was pouredinto ice-water (20 mL) and then extracted with ethyl acetate (25 mL×2).The organic layers were combined and washed with brine (50 mL) beforeconcentration. The residue was purified by flash chromatography elutingwith 0-100% EtOAc/hexanes to provide the title compounds.

Second and third eluting isomers isolated as a mixture (Example 55).¹H-NMR (400 MHz; CDCl₃): δ 7.33-7.29 (m, 1H), 7.00-6.93 (m, 2H),6.92-6.88 (m, 1H), 6.05-5.60 (m, 1H), 4.99-4.65 (m, 1H), 4.10-4.00 (m,1H), 2.75-2.57 (m, 1H), 2.46-2.30 (m, 1H), 2.16-2.08 (m, 1H), 2.06-1.96(m, 2H), 1.84-1.74 (m, 2H), 1.72-1.48 (m, 1H), 1.12-1.08 (m, 3H). LC-MS(Method C): m/z=298.3 [M+H]⁺, 1.74 min.

Fourth eluting isomer isolated as a single stereoisomer (Example 56):¹H-NMR (400 MHz; CDCl₃): δ 7.31 (dd, J=8.0, 5.9 Hz, 1H), 7.00-6.93 (m,2H), 6.90 (dt, J=9.9, 2.1 Hz, 1H), 5.94 (t, J=56.4 Hz, 1H), 4.66 (d,J=9.2 Hz, 1H), 4.11-4.03 (m, 1H), 2.69-2.58 (m, 1H), 2.42 (dd, J=13.2,8.9 Hz, 1H), 2.14-2.03 (m, 3H), 1.86-1.66 (m, 3H), 1.08 (t, J=7.5 Hz,3H). LC-MS (Method C): m/z=298.3 [M+H]⁺, 1.73 min.

Examples 57 and 58(8S)-2-(difluoromethyl)-2-ethyl-5-(3-fluorophenyl)-5,6,7,8-tetrahydro-1H-pyrrolizin-3-one

The title compounds were prepared using(5S)-5-but-3-enylpyrrolidin-2-one employing the procedures described forthe synthesis of Examples 55 and 56 followed by purification by flashchromatography eluting with 0-100% EtOAc/hexanes.

The first eluting isomer isolated as a single stereoisomer (Example 57).¹H-NMR (400 MHz; CDCl₃): δ 7.33-7.29 (m, 1H), 7.02 (ddt, J=7.7, 1.6, 0.8Hz, 1H), 6.97-6.91 (m, 2H), 5.98 (t, J=56.5 Hz, 1H), 4.99-4.95 (m, 1H),4.08-4.01 (m, 1H), 2.75-2.67 (m, 1H), 2.31 (dd, J=14.0, 5.9 Hz, 1H),2.20-2.14 (m, 2H), 2.04-1.96 (m, 1H), 1.89 (td, J=14.2, 6.8 Hz, 1H),1.77-1.70 (m, 1H), 1.57-1.47 (m, 1H), 1.11 (t, J=7.5 Hz, 3H). LC-MS(Method C): m/z=298.3 [M+H]⁺, 1.81 min.

The second and third eluting isomers isolated as a mixture (Example 58).¹H-NMR (400 MHz; CDCl₃): δ 7.33-7.29 (m, 1H), 7.00-6.93 (m, 2H),6.92-6.88 (m, 1H), 6.05-5.60 (m, 1H), 4.99-4.65 (m, 1H), 4.10-4.00 (m,1H), 2.75-2.57 (m, 1H), 2.46-2.30 (m, 1H), 2.16-2.08 (m, 1H), 2.06-1.96(m, 2H), 1.84-1.74 (m, 2H), 1.72-1.48 (m, 1H), 1.12-1.08 (m, 3H). LC-MS(Method C): m/z=298.3 [M+H]⁺, 1.77 min.

Other compound(s) shown above in Table 1 were prepared according to theExamples above and/or general procedures described herein.

In Vitro Assay 1 Receptor Interacting Protein Kinase 1 Inhibition byCompounds of Formula I

Fluorescent Polarization Binding (FP Binding) assay (Berger S. B. et al.(2015) Cell Death Discovery, 1: 15009; Maki J. L. et al. (2012) AnalBiochem., 427(2): 164-174) was performed in polystyrene low volume384-well black plate, at Room Temperature (RT) in a final volume of 10.1μL/well using 10 nM of GST-human receptor interacting protein kinase 1fusion (8-327) enzyme and 5 nM of fluorescent-labeled ligand(14-(2-{[3-({2-{[4-(cyanomethyl)phenyl]amino}-6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-4-pyrimidinyl}amino)propyl]amino}-2-oxoethyl)-16,16,18,18-tetramethyl-6,7,7a,8a,9,10,16,18-octahydrobenzo[2″,3″]indolizino[8″,7″:5′,6′]pyrano[3′,2′:3,4]pyrido[1,2-a]indol-5-ium-2-sulfonate.

Test compounds were serially diluted in DMSO at 100 fold finalconcentrations in the assay (1% DMSO final). In each well of a 384-wellPlate were dispensed 0.1 μL of compound solution (or DMSO for controls)followed by 5 μL of GST-human receptor interacting protein kinase 1fusion (8-327) enzyme at twice the final concentrations in assay buffer(50 mM HEPES pH 7.5, 10 mM NaCl, 50 mM MgCl₂, 0.02% CHAPS, 0.5 mM DTTand 0.01% Pluronic F127). For negative control the enzyme addition wasreplaced by assay buffer only.

After addition of 5 μL of fluorescent-labeled ligand at twice the finalconcentrations in assay buffer, the plate was incubated at RT for 30min. At the end, the binding was measured as FP value with the Envision(PerkinElmer) plate reader using filter for an excitation λ=531 nm FPand an emission λ=595 nm FP (S & P-pol).

Test compound inhibition was expressed as percent inhibition of internalassay controls. For concentration response curves, normalized data isfit and IC₅₀ determined using XL-fit (IDBS) for Excel. IC₅₀ wereaveraged to determine a mean value, for a minimum of two independentexperiments.

Receptor interacting protein kinase 1 activity of exemplary compoundswas determined according to the above general procedures. Results aresummarized in Table 3.

TABLE 3 No IC₅₀ 1 +++ 2 ++ 3 +++ 4 ++ 5 +++ 6 +++ 7 +++ 8 ++ 9 ++ 10 +++11 +++ 12 +++ 13 +++ 14 +++ 15 ++ 16 +++ 17 +++ 18 +++ 19 +++ 20 +++ 21+++ 22 +++ 23 +++ 24 +++ 25 +++ 26 ++ 27 +++ 28 +++ 29 +++ 30 +++ 31 +++32 +++ 33 +++ 34 ++ 35 +++ 36 ++ 37 +++ 38 ++ 39 +++ 40 +++ 41 ++ 42 +++43 ++ 44 +++ 45 +++ 46 ++ 47 +++ 48 ++ 49 ++ 50 +++ 51 ++ 52 +++ 53 ++54 +++ 55 +++ 56 +++ 57 +++ 58 +++ +++ indicates IC₅₀ < 1 μM ++indicates 1 μM ≤ IC₅₀ < 30 μM + indicates IC₅₀ ≥ 30 μM

Although various embodiments of the disclosure are disclosed herein,many adaptations and modifications may be made within the scope of thedisclosure in accordance with the common general knowledge of thoseskilled in this art. Such modifications include the substitution ofknown equivalents for any aspect of the disclosure in order to achievethe same result in substantially the same way. Numeric ranges areinclusive of the numbers defining the range. The word “comprising” isused herein as an open-ended term, substantially equivalent to thephrase “including, but not limited to” and the word “comprises” has acorresponding meaning. As used herein, the singular forms “a”, “an” and“the” include plural referents unless the context clearly dictatesotherwise. Thus, for example, reference to “a thing” includes more thanone such thing. Citation of references herein is not an admission thatsuch references are prior art to the present disclosure. Any prioritydocument(s) and all publications, including but not limited to patentsand patent applications, cited in this specification are incorporatedherein by reference as if each individual publication were specificallyand individually indicated to be incorporated by reference herein and asthough fully set forth herein. The disclosure includes all embodimentsand variations substantially as hereinbefore described and withreference to the examples and drawings.

The invention claimed is:
 1. A compound of Formula I:

or a pharmaceutically acceptable salt, stereoisomer, or mixture ofstereoisomers thereof, wherein: Y is N or CH; n is 1 or 2; m is 0, 1, 2,3, 4, or 5; p is 0, 1, 2, or 3; A is aryl, heteroaryl, C₃₋₁₀ cycloalkyl,or heterocyclyl; each of R¹ and R² is independently hydrogen, deuterium,halo, C₁₋₁₂ alkyl, C₁₋₁₂ alkenyl, C₁₋₁₂ alkynyl, C₁₋₁₂ alkoxy, C₁₋₁₂haloalkyl, C₁₋₁₂ haloalkoxy, C₃₋₁₀ cycloalkyl, heterocyclyl, heteroarylor aryl; wherein each C₁₋₁₂ alkyl, C₁₋₁₂ alkenyl, C₁₋₁₂ alkynyl, C₁₋₁₂alkoxy, C₁₋₁₂ haloalkyl, C₁₋₁₂ haloalkoxy, C₃₋₁₀ cycloalkyl,heterocyclyl, heteroaryl, and aryl is optionally substituted with one,two, three, four, or five Z¹; or R¹ and R² taken together with the atomsto which they are attached form a C₃₋₁₀ cycloalkyl; wherein the C₃₋₁₀cycloalkyl is optionally substituted with one, two, three, four, or fiveZ²; R³ in each instance is independently deuterium, halo, hydroxy,cyano, nitro, azido, oxo, C₁₋₁₂ alkyl, —OR⁵, C₁₋₁₂ alkoxy, C₂₋₁₂alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂ haloalkyl, C₁₋₁₂ haloalkoxy, C₃₋₁₀cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R⁴, —C(═O)OR⁴,—OC(═O)OR⁴, —OC(═O)R⁴, —C(═O)NR⁴R⁵, —OC(═O)NR⁴R⁵, —NR⁴C(═O)NR⁵R⁶,—S(═O)₁₋₂R⁴, —S(═O)₁₋₂OR⁴, —OS(═O)₁₋₂R⁴, —S(═O)₁₋₂ NR⁴, —NR⁴S(═O)₁₋₂R⁵,—NR⁴S(═O)₁₋₂NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵, or —NR⁴C(═O)OR⁵; wherein eachC₁₋₁₂ alkyl, C₁₋₁₂ alkoxy, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂haloalkyl, C₁₋₁₂ haloalkoxy, C₃₋₁₀ cycloalkyl, heterocyclyl, aryl, andheteroaryl is optionally substituted with one, two, three, four, or fiveZ³; R⁴, R⁵, and R⁶ in each instance are independently C₁₋₁₂ alkyl, C₁₋₁₂alkenyl, C₁₋₁₂ alkynyl, C₁₋₁₂ haloalkyl, C₃₋₁₀ cycloalkyl, heterocyclyl,heteroaryl, or aryl; wherein each C₁₋₁₂ alkyl, C₁₋₁₂ alkenyl, C₁₋₁₂alkynyl, C₁₋₁₂ haloalkyl, C₃₋₁₀ cycloalkyl, heterocyclyl, heteroaryl,and aryl is optionally substituted with one, two, three, four, or fiveZ⁴; or two of R⁴, R⁵, and R⁶ taken together with the atoms to which theyare attached form a heterocyclyl; wherein the heterocyclyl is optionallysubstituted with one, two, three, four, or five Z⁵; R¹⁴ is bonded toeither ring of the fused bicyclic ring and, in each instance, isindependently halo or haloalkyl, or two R¹⁴ bonded to the same carbonatom may be taken together with the atom to which they are attached toform a C₃₋₁₀ cycloalkyl or heterocyclyl; wherein the C₃₋₁₀ cycloalkyl orheterocyclyl is optionally substituted with one, two, three, four, orfive Z⁶; each of Z¹, Z², Z³, Z⁴, Z⁵, and Z⁶ are independently deuterium,halo, hydroxy, cyano, nitro, azido, C₁₋₁₂ alkyl, C₁₋₁₂ alkenyl, C₁₋₁₂alkynyl, C₁₋₁₂ alkoxy, C₁₋₁₂ haloalkyl, C₁₋₁₂ haloalkoxy, C₃₋₁₀cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R¹¹, —C(═O)OR¹¹,—OC(═O)OR¹¹, —OC(═O)R¹¹, —C(═O)NR¹¹R¹², —OC(═O)NR¹¹R¹²,—NR¹¹C(═O)NR¹²R¹³, —S(═O)₁₋₂R¹¹, —S(═O)₁₋₂OR¹¹, —S(═O)₁₋₂NR¹¹,—NR¹¹S(═O)₁₋₂R¹², —NR¹¹S(═O)₁₋₂NR¹²R¹³, —NR¹¹R¹², —NR¹¹C(═O)R¹², or—NR¹¹C(═O)OR¹²; wherein each C₁₋₁₂ alkyl, C₁₋₁₂ alkenyl, C₁₋₁₂ alkynyl,C₁₋₁₂ alkoxy, C₁₋₁₂ haloalkyl, C₁₋₁₂ haloalkoxy, C₃₋₁₀ cycloalkyl,heterocyclyl, aryl, and heteroaryl is optionally substituted with one,two, or three substituents independently selected from deuterium, halo,hydroxy, cyano, amino, nitro, azido, oxo, C₁₋₁₂ alkyl, C₁₋₁₂ alkoxy,C₁₋₁₂ haloalkyl, C₁₋₁₂ haloalkoxy, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀cycloalkyl, heterocyclyl, aryl, and heteroaryl; and R¹¹, R¹², and R¹³ ineach instance are independently C₁₋₁₂ alkyl, C₁₋₁₂ alkenyl, C₁₋₁₂alkynyl, C₁₋₁₂ alkoxy, C₃₋₁₀ cycloalkyl, heterocyclyl, heteroaryl, oraryl; wherein each C₁₋₁₂ alkyl, C₁₋₁₂ alkenyl, C₁₋₁₂ alkynyl, C₁₋₁₂alkoxy, C₃₋₁₀ cycloalkyl, heterocyclyl, heteroaryl, and aryl isoptionally substituted with one, two, three, four, or five Z¹¹; or twoof R¹¹, R¹², and R¹³ are taken together with the atoms to which they areattached to form a heterocyclyl; wherein the heterocyclyl is optionallysubstituted with one, two, three, four or five Z¹²; wherein each of Z¹¹and Z¹² is independently deuterium, halo, hydroxy, cyano, oxo, amino orC₁₋₁₂ alkyl; wherein the C₁₋₁₂ alkyl is optionally substituted with one,two or three halo, hydroxyl, amino or oxo, provided that when n is 1, Yis CH, and both of R¹ and R² are hydrogen, then A is not heterocyclylsubstituted with oxo; and when n is 2, Y is CH and one of R¹ or R² isiodo, or both of R¹ or R² are hydrogen, then A is not 4-chlorophenyl,2,6-difluoropyridin-3-yl, phenyl, or phenyl substituted with 1, 2 or 3fluoro; and the compound is not chosen from(3R,8aR)-6-chloro-3-(4-fluorophenyl)hexahydroindolizin-5(1H)one;(3R,6S,8aS)-6-methyl-3-phenylhexahydroindolizin-5(1H)-one;hexahydro-6-methyl-3-phenyl-5(1H)-indolizinone; and6-[(2-bromo-1H-indol-3-yl)methyl]hexahydro-3-(4-hydroxyphenyl)-5(1H)-indolizinone.2. The compound of claim 1, wherein Y is N.
 3. The compound of claim 1,wherein Y is CH.
 4. The compound of claim 1, wherein n is
 1. 5. Thecompound of claim 1, wherein n is
 2. 6. The compound of claim 1, whereineach of R¹ and R² is independently hydrogen, deuterium, C₁₋₁₂ haloalkyl,or C₁₋₁₂ alkyl.
 7. The compound of claim 6, wherein each of R¹ and R² isindependently C₁₋₁₂ haloalkyl or C₁₋₁₂ alkyl.
 8. The compound of claim7, wherein one of R¹ and R² is methyl and the other of R¹ and R² isethyl.
 9. The compound of claim 7, wherein R¹ and R² are both methyl.10. The compound of claim 1, wherein m is 1, 2, or
 3. 11. The compoundof claim 1, wherein R³ in each instance is independently deuterium,halo, hydroxy, cyano, nitro, or C₁₋₁₂ alkyl.
 12. The compound of claim1, wherein m is 1 or 2, and R³ in each instance is independentlydeuterium, halo, hydroxy, cyano, nitro, or C₁₋₁₂ alkyl.
 13. The compoundof claim 1, wherein R³ in each instance is independently halo or cyano.14. The compound of claim 13, wherein R³ in each instance isindependently fluoro or cyano.
 15. The compound of claim 1, wherein m is0.
 16. A compound selected from:

second eluting enantiomer,

and pharmaceutically acceptable salts, stereoisomers, and mixtures ofstereoisomers thereof.
 17. A pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of claim 1.